@article {pmid42134046,
year = {2026},
author = {Chu, TDX and Hui, LM and Khatri, N and Jean Chen, J},
title = {Resilience to mid-to-late-life depression as a risk factor for Alzheimer's disease: Physiological factors and the role of neuroimaging.},
journal = {Neurobiology of aging},
volume = {166},
number = {},
pages = {1-13},
doi = {10.1016/j.neurobiolaging.2026.05.004},
pmid = {42134046},
issn = {1558-1497},
abstract = {Depression and Alzheimer's Disease (AD) are both diagnosed in women twice as often as in men. Moreover, a history of untreated depression confers a 2-to-5-fold increase in the risk of developing dementia. Finally, biological factors such as sex differences in immune response increase rates of depressive pathology among women. Importantly, the prevalence of mid-to-late-life depression (MLD) worldwide and its misdiagnosis due to clinical overlap with AD hinder accurate assessment and timely treatment of depression among older adults. Correct diagnosis of depression and AD using neuroimaging will enable early adoption of appropriate management, which will improve cognitive resilience. In the context of neural resilience in late-life depression, this review discusses the involvement of sex-related risk factors such as differences in immune response, and the importance of understanding the mid-life neurological signature of depression. We focus on the role of diffusion-weighted magnetic resonance imaging (MRI), which is also specifically linked to the presence of neuroinflammation in depression and the ability to distinguish it from AD despite cognitive overlaps in clinical manifestation. This review highlights the importance of sex differences in promoting resilience against MLD and AD-related declines, and supports neuroimaging as a feasible approach to advance our understanding of the role of neuroinflammation in both depression and Alzheimer's disease as a sex-dependent phenomenon.},
}

@article {pmid42134309,
year = {2026},
author = {Lee, J and Zhu, Y and Tseng, HR},
title = {Bioorthogonal Click Chemistry-Enabled Enrichment of Extracellular Vesicles for Integrated Molecular and Functional Liquid Biopsy§.},
journal = {Accounts of chemical research},
volume = {},
number = {},
pages = {},
doi = {10.1021/acs.accounts.6c00091},
pmid = {42134309},
issn = {1520-4898},
abstract = {ConspectusExtracellular vesicles (EVs) are lipid bilayer-enclosed nanoparticles released by virtually all cells, carrying protected lipids, nucleic acids, proteins, and active enzymes that faithfully reflect the physiological and pathological states of their cellular origins. Tumor- and neuron-derived EVs are abundantly present in peripheral blood, even at early disease stages, and thus represent highly attractive substrates for liquid biopsy. However, the clinical translation of EV-based diagnostics has been constrained by a central challenge: the inability to selectively enrich disease-relevant EVs from a vast background of normal EVs with sufficient specificity, efficiency, and compatibility for seamless integration with downstream molecular and functional analyses. Conventional physical isolation approaches generate heterogeneous EV mixtures that dilute disease-specific signals, whereas traditional immunoaffinity capture often suffers from nonspecific interactions and low recovery due to sparse and heterogeneous antigen density on EV membranes.To overcome these limitations, our laboratory has developed a chemical biology solution utilizing the bioorthogonal inverse-electron-demand Diels-Alder reaction between trans-cyclooctene (TCO) and tetrazine (Tz). By labeling tumor or neuronal EVs in plasma with TCO-grafted antibodies and covalently immobilizing them onto Tz-functionalized substrates, our three EV enrichment platforms, namely, EV Click Chips, EV Click Beads, and EV Click MagBeads, enable rapid, irreversible, and highly specific capture of defined EV subpopulations. These click chemistry-mediated enrichment strategies reduce nonspecific binding, markedly improve capture efficiency, and preserve EV integrity, providing a robust foundation for downstream genetic, proteomic, and functional analyses. Building on this chemical biology solution, we established three complementary EV assay modalities. Platform #1, the EV Digital Scoring Assay, couples click chemistry-mediated EV enrichment with RT-digital PCR to quantify tumor-specific mRNAs or oncogenic mutations. This "enrich-then-count" strategy has demonstrated strong clinical utility in early detection of hepatocellular carcinoma (HCC), molecular staging of prostate cancer, and detection of actionable gene alterations in pancreatic cancer and Ewing sarcoma. A refined version enables real-time HCC treatment-response monitoring, outperforming serum AFP and radiographic criteria in monitoring treatment responses. Platform #2, the EV Surface Protein Assay, uses antibody-directed click enrichment followed by immuno-PCR or RT-qPCR to quantify tumor-specific EV subpopulations. Analogous to tissue immunohistochemistry but executed in a liquid-biopsy format, this assay has shown accuracy in early detection of HCC, pancreatic ductal adenocarcinoma, and epithelial ovarian cancer and supports longitudinal monitoring in prostate and thyroid cancers. Platform #3, the EV Protease Activity Assay, extends EV analysis into functional biology by measuring enzymatic activities preserved within enriched EVs. In osteosarcoma, matrix metalloproteinase activity profiles stratified localized versus metastatic disease and tracked therapeutic response. In neurology, quantifying β-secretase activity in neuronal EVs enabled highly accurate detection of early Alzheimer's disease and correlated with cognitive performance.Together, these TCO-Tz click chemistry-enabled platforms provide a modular, robust, and clinically adaptable toolkit for noninvasive EV-based diagnostics. By uniting chemical precision with biological and clinical relevance, this framework advances the broader vision of real-time, disease-specific liquid biopsy across oncology and neurodegeneration, laying the foundation for next-generation integrated diagnostic systems.},
}

@article {pmid42134480,
year = {2026},
author = {Wu, Q and Cui, X and Liu, X and Yuan, X and Wang, P and Li, H and Xiu, R},
title = {Tetramethylpyrazine improving cerebral microcirculation in Alzheimer's Disease mice.},
journal = {Brain research bulletin},
volume = {},
number = {},
pages = {111936},
doi = {10.1016/j.brainresbull.2026.111936},
pmid = {42134480},
issn = {1873-2747},
abstract = {Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligusticum chuanxiong), has been demonstrated to improve tissue microcirculation. However, direct in vivo monitoring of cerebral microcirculation is still challenging due to the presence and thickness of the skull. In this study, we constructed a visualized mouse cranial window and utilized photoacoustic microscopy, laser speckle imaging, and Laser Doppler flowmetry to investigate the effect of Tetramethylpyrazine on cortical microvascular function in normal mice, AD mice, and Tetramethylpyrazine-treated AD mice. Our results revealed impaired cerebral microvascular perfusion in AD mice, including significant reductions in blood flow velocity, oxygen saturation, and metabolic rate of oxygen. Tetramethylpyrazine treatment improved cortical microvascular function in AD mice, with endothelium-derived microvascular signals playing a key role in microvascular rhythmic motion. These findings suggest that Tetramethylpyrazine has the ability to enhance cortical microcirculation in AD mice through multiple mechanisms, particularly through endothelial improvement. Tetramethylpyrazine may serve as a potential candidate drug for AD treatment, and photoacoustic microscopy holds promise in the clinical observation of cortical microcirculation in AD.},
}

@article {pmid42134886,
year = {2026},
author = {Chinnathambi, S and Rangappa, N},
title = {Biosimilars: Antibody and nanobody-based therapeutic approaches towards protein misfolding diseases.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {157-195},
doi = {10.1016/bs.apcsb.2025.10.014},
pmid = {42134886},
issn = {1876-1631},
mesh = {Humans ; *Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology ; *Proteostasis Deficiencies/drug therapy/metabolism/pathology ; *Single-Domain Antibodies/therapeutic use ; Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Alzheimer Disease/drug therapy/metabolism/pathology ; tau Proteins/metabolism/antagonists & inhibitors/immunology ; *Neurodegenerative Diseases/drug therapy/metabolism ; Animals ; alpha-Synuclein/metabolism/antagonists & inhibitors ; *Parkinson Disease/drug therapy/metabolism/pathology ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, and Parkinson's disease, are characterized by progressive neuronal dysfunction and degeneration. These conditions often share pathological hallmarks such as protein misfolding, oxidative stress, neuroinflammation, and mitochondrial dysfunction. This review focuses on key pathological players like Tau and Amyloid-beta in Alzheimer's disease, highlighting their roles in microtubule destabilization, synaptic dysfunction, and neuronal death. The interplay between oxidative stress and these proteinopathies exacerbates neurodegeneration. Recent advances in therapeutic strategies are also explored, particularly the promise of biosimilars, cost-effective alternatives to biologics, targeting pathological hallmarks in neurodegenerative diseases. Biosimilars targeting Tau and Amyloid-beta in Alzheimer's disease, and alpha-synuclein in Parkinson's disease, hold the potential to improve treatment accessibility and reduce economic burdens. However, their development is still in its early stages. This review underscores the urgent need for innovative, affordable, and globally accessible therapeutic solutions to address the rising burden of neurodegenerative diseases.},
}

Humans
*Biosimilar Pharmaceuticals/therapeutic use/chemistry/pharmacology
*Proteostasis Deficiencies/drug therapy/metabolism/pathology
*Single-Domain Antibodies/therapeutic use
Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Alzheimer Disease/drug therapy/metabolism/pathology
tau Proteins/metabolism/antagonists & inhibitors/immunology
*Neurodegenerative Diseases/drug therapy/metabolism
Animals
alpha-Synuclein/metabolism/antagonists & inhibitors
*Parkinson Disease/drug therapy/metabolism/pathology

@article {pmid42134887,
year = {2026},
author = {Chinnathambi, S},
title = {Induced-pluripotent stem cell-derived immunotherapy for Tau and Alzheimer's disease.},
journal = {Advances in protein chemistry and structural biology},
volume = {151},
number = {},
pages = {197-224},
doi = {10.1016/bs.apcsb.2025.10.005},
pmid = {42134887},
issn = {1876-1631},
mesh = {*Alzheimer Disease/therapy/immunology/pathology/metabolism ; Humans ; *Induced Pluripotent Stem Cells/cytology/metabolism/immunology ; *tau Proteins/immunology/metabolism ; *Immunotherapy ; Animals ; },
abstract = {Neurodegenerative diseases, such as Alzheimer's disease, are characterized by progressive neuronal death and functional decline. Key pathological hallmarks of Alzheimer's disease include the deposition of aggregated amyloid-β (Aβ) proteins into extracellular plaques and the accumulation of hyperphosphorylated Tau protein into intracellular aggregates. These toxic species triggers neuroinflammation through interactions with glial cells, further exacerbating neurodegeneration. This study explores the potential of induced pluripotent stem cells (iPSCs) in disease modelling, focusing on their application in modelling Alzheimer's disease pathology and therapeutic screening. Additionally, the development of advanced 3D culture systems and organoids offers insights into human-specific Alzheimer's disease mechanisms, overcoming limitations of traditional 2D and animal models. The focus is on the role of microglial polarization in neuroinflammation and its potential therapeutic modulation, offering a promising approach for the treatment of neurodegenerative diseases.},
}

*Alzheimer Disease/therapy/immunology/pathology/metabolism
Humans
*Induced Pluripotent Stem Cells/cytology/metabolism/immunology
*tau Proteins/immunology/metabolism
*Immunotherapy
Animals

@article {pmid42135923,
year = {2026},
author = {Mia, E and Hossain, MA and Bristy, AH and Hossan, R and Asif, U and Sherwani, AK and Alshahrani, MY and Selim, S and Rakib, IH and Yana, NT and Akter, K and Hasan, MSA},
title = {Neuroprotective Properties of Litchi chinensis and Its Phytochemicals in Preclinical Models of Alzheimer's Disease.},
journal = {Brain and behavior},
volume = {16},
number = {5},
pages = {e71474},
doi = {10.1002/brb3.71474},
pmid = {42135923},
issn = {2162-3279},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; *Litchi/chemistry ; Animals ; *Neuroprotective Agents/pharmacology ; Disease Models, Animal ; *Phytochemicals/pharmacology ; *Plant Extracts/pharmacology ; Humans ; Rats ; Oxidative Stress/drug effects ; Mice ; Amyloid beta-Peptides/metabolism ; },
abstract = {PURPOSE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder involving amyloid-β deposition, tau hyperphosphorylation, oxidative stress, and neuroinflammation. This review systematically evaluates the neuroprotective effects of Litchi chinensis and its phytochemicals against AD, focusing on modulation of Aβ accumulation, tau pathology, oxidative stress, neuroinflammation, apoptosis, and synaptic dysfunction using available preclinical evidence.

METHOD: A systematic literature search was conducted in PubMed, Scopus, Web of Science, ScienceDirect, and Google Scholar up to August 2025 using relevant keywords. Studies investigating neuroprotective effects of Litchi chinensis extracts or compounds in in vitro or in vivo AD models were included, while unrelated studies, duplicates, abstracts, and non-full-text articles were excluded.

RESULTS: Litchi chinensis extracts and phytochemicals demonstrated broad neuroprotective actions. In triple-transgenic mice, oligonol treatment (0.25-0.50 mg/mL) significantly reduced amyloid precursor protein (APP), β-secretase, and amyloid-β levels, while also decreasing tau hyperphosphorylation. Seed extracts (0.7-2.8 g/kg/day) reduced amyloid-β accumulation and neuronal injury in Sprague-Dawley rats. Anti-inflammatory effects were evident through decreased tumor necrosis factor-α, IL-1β, IL-6, and interferon gamma, alongside increased IL-4. Antioxidant defenses were enhanced via upregulation of antioxidant enzymes such as glutathione peroxidase-1 and superoxide dismutase-2, while apoptosis was suppressed by increasing Bcl-2 and reducing Bax and caspase activity. Synaptic integrity was preserved through upregulation of PSD95, synaptophysin, and serotonin receptor proteins, resulting in improved learning and memory in AD models. Additional benefits included enhanced mitochondrial and proteasomal activity, alleviation of endoplasmic reticulum (ER) stress, and induction of neurotrophic factors like insulin-like growth factor 2 and fibroblast growth factor 21.

CONCLUSION: Litchi chinensis demonstrates a multitargeted neuroprotective role, making it a promising natural therapeutic candidate for Alzheimer's management. However, as most findings are limited to preclinical models, further clinical studies are necessary to validate efficacy, ensure safety, and explore its translational potential.},
}

*Alzheimer Disease/drug therapy/metabolism
*Litchi/chemistry
Animals
*Neuroprotective Agents/pharmacology
Disease Models, Animal
*Phytochemicals/pharmacology
*Plant Extracts/pharmacology
Humans
Rats
Oxidative Stress/drug effects
Mice
Amyloid beta-Peptides/metabolism

@article {pmid42136137,
year = {2026},
author = {Bao, L and Zhao, F and Xu, W and Jiang, P and Zhang, Y and Luo, Y and Guan, W and Li, M and Chen, Q and Zhang, L and Kuang, H and Li, J and Liu, Y},
title = {Pharmacodynamics and mechanisms of triterpene components from the leaves of Astragalus mongholicus Bunge in the treatment of Alzheimer's disease.},
journal = {Natural product research},
volume = {},
number = {},
pages = {1-9},
doi = {10.1080/14786419.2026.2671969},
pmid = {42136137},
issn = {1478-6427},
abstract = {This study investigates the therapeutic potential and underlying mechanisms of triterpenoids (TR) derived from the leaves of Astragalus mongholicus Bunge for the treatment of Alzheimer's disease (AD). Eighteen triterpenoid compounds were identified in the TR fraction using UPLC-Q-TOF-MS. In the 3 × Tg-AD transgenic mouse model, the therapeutic efficacy of TR was assessed using a comprehensive approach that included the Morris water maze, histopathological analysis, transmission electron microscopy, and Western blotting. The findings revealed that TR significantly improved spatial learning and memory impairments, reduced hippocampal neuronal degeneration, and diminished the deposition of phosphorylated Tau (p-Tau) protein. Ultrastructural examination further confirmed that TR preserved mitochondrial integrity. Mechanistic studies showed that TR upregulated key mitophagy-related proteins in both PINK1/Parkin-dependent and -independent pathways. In conclusion, TR exerts neuroprotective effects by activating mitophagy through multiple pathways, highlighting its potential as a promising therapeutic candidate for AD. This study not only provides experimental evidence for the therapeutic potential of natural products targeting mitophagy in Alzheimer's disease but also expands the medicinal development value of the leaves of Astragalus mongholicus Bunge.},
}

@article {pmid42136262,
year = {2026},
author = {Khan, MA and Khan, ZA and Shoeb, F and Siddiqui, Z and Pandey, G and Fatima, G and Khan, RH and Khan, MM},
title = {Role of De Novo Lipogenesis in Neurodegeneration and Neurogenesis Disruption in Alzheimer's Disease and Treatment Perspective.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X423516260216052123},
pmid = {42136262},
issn = {1875-6190},
abstract = {Progressive neurodegeneration, decline in neurogenesis, and cognitive dysfunction alongside amyloid-β plaque and neurofibrillary tangle formation are prominent pathological features of Alzheimer's Disease (AD). Although the underlying mechanism remains unclear, evidence suggests that surplus intracellular lipids/fatty acids could be the primary mediators. In this regard, increased levels of Saturated Fatty Acids (SFAs), Monounsaturated Fatty Acids (MUFAs), their triglyceride and ceramide derivatives have been reported in the brain of patients with AD. Further, converging evidence from basic and clinical studies suggests that de novo lipogenesis could be the main source of lipid/fatty acid accumulation in the brains of patients with AD. Although elevated cholesterol has long been suggested to induce inflammation and neurodegenera-tion in AD, recent evidence suggests that the effects of SFAs and their lipid derivatives, particularly ceramides, could be more detrimental. Consequently, de novo lipogenesis inhibitors could be the potential therapeutic targets for the early intervention in AD. Intriguingly, several studies have shown that treatment with various natural or synthetic compounds, which inhibit de novo lipogenesis, effectively reduced neurodegeneration, cognitive dysfunction, and inflammation in the model animals of AD. These compounds also increased neurogenesis while reducing lipid/fatty acid accumulation, suggesting that blocking lipid/fatty acid biosynthesis by inhibiting de novo lipogenesis could be an effective strategy in treating AD. Thus, while the study discusses the effects of various FDA-approved AD drugs and selected natural and synthetic inhibitors of de novo lipogenesis on neurodegeneration and neurogenesis in model animals, the doors are open for conducting clinical trials in patients with AD.},
}

@article {pmid42136266,
year = {2026},
author = {Gupta, S and Nihal, PM and Jawaid, T and Ashesh, AM and Bhise, MR and Rawat, M and Lohidasan, S and Wal, P and Kumar, A and Kumar, D and Gasmi, A},
title = {Exploring Mitochondrial Dysfunction and Protective Therapeutic Approaches to Counteract Its Role in Alzheimer's Disease Progression.},
journal = {Current neuropharmacology},
volume = {},
number = {},
pages = {},
doi = {10.2174/011570159X419571260226033536},
pmid = {42136266},
issn = {1875-6190},
abstract = {Alzheimer's disease (AD) is the primary cause of dementia, characterized by a progres-sive decrease in mental abilities and the accumulation of amyloid-beta (Aβ) peptides in the brain. The combination of these peptides leads to the development of neuritic plaques and neurofibrillary tangles that disrupt neural communication and eventually lead to the loss of neurons. One of the fac-tors that are involved in the development of AD is mitochondrial dysfunction. Disrupted function-ing of mitochondria leads to the production of less energy by the cells, increased oxidative stress, and accelerates the neurodegeneration process. Neurons that carry out their mitochondrial functions normally are required to keep the balance of calcium, in a reasonable energy production, and in the survival of the cells. Mitophagy, which guarantees the clearing of damaged mitochondria, is im-paired in AD. Cholinesterase blockers and NMDA receptor blockers are currently used as treat-ments, but these are not aimed at the underlying pathophysiology of the condition. New treatment approaches that are aimed at enhancing mitochondrial health, in contrast, are viable at providing a potential to decelerate or alter mitochondrial AD progression. The goals of these approaches include enhancement of the mitophagy process, alleviation of oxidative stress, and preservation of mito-chondrial health, which may disrupt major pathological events such as Aβ aggregation and tau hy-perphosphorylation. By concentrating on the replacement of mitochondria, scientists are moving in the right direction to develop therapies that will not only help control the symptoms but also cure the disease.},
}

@article {pmid42136278,
year = {2026},
author = {Sharma, A and Mittal, V and Sharma, D and Deswal, G and Das, A and Guarve, K and Grewal, AS},
title = {Therapeutic Insights into Natural Products for Modulating Neurodegenerative Disease Pathways.},
journal = {Central nervous system agents in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715249405308251210104405},
pmid = {42136278},
issn = {1875-6166},
abstract = {INTRODUCTION: Neurodegenerative Disorders (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and Amyotrophic Lateral Sclerosis (ALS), are chronic and progressive conditions marked by the gradual loss of neuronal structure and function. These disorders lead to cognitive, motor, and sensory decline, significantly reducing quality of life and posing a major global health burden due to rising healthcare costs and the absence of curative therapies. This review aims to comprehensively explore the therapeutic potential of natural products in targeting cellular and molecular mechanisms underlying NDs, highlighting their neuroprotective roles and potential for disease modification.

METHODS: A comprehensive literature review was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar. Peer-reviewed articles, clinical trials, and experimental studies were analyzed to evaluate the therapeutic potential of natural products and their bioactive compounds in the management of NDs.

RESULTS: ND pathogenesis involves oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation, ultimately leading to neuronal death. Current therapies largely provide symptomatic relief without altering disease progression. Natural products from plants, fungi, and marine sources demonstrate strong neuroprotective potential through multitargeted mechanisms. Bioactive compounds such as flavonoids, alkaloids, terpenoids, and polyphenols exhibit antioxidant, anti-inflammatory, anti-apoptotic, and neuroprotective activities. Key molecules, including curcumin, resveratrol, luteolin, quercetin, and catechins, modulate signaling pathways such as NF-κB, MAPK, PI3K/AKT, Nrf2, apoptosis, and autophagy, thereby reducing amyloid-beta aggregation, protecting dopaminergic neurons, improving mitochondrial function, and enhancing cognition in preclinical and clinical studies.

DISCUSSION: Natural products represent promising candidates for disease modification in NDs due to their multi-pathway actions and relatively low toxicity. However, major limitations, such as poor bioavailability, pharmacokinetic variability, and the lack of standardized formulations, hinder clinical translation. Innovative strategies, including advanced drug-delivery systems, structural modifications, and synergistic formulations, are needed to overcome these barriers.

CONCLUSION: Natural products hold significant therapeutic potential in managing neurodegenerative diseases by targeting multiple pathological mechanisms. Their integration into ND treatment could provide safer and more effective alternatives, but further well-designed clinical trials are essential to establish their efficacy and facilitate clinical application.},
}

@article {pmid42136282,
year = {2026},
author = {Singh, P and Bhardwaj, S and Nagarajan, K},
title = {Development and Assessment of Phytoconstituents-based Nanoemulsion as a Potent Combined Therapy for Neuroprotection in Scopolamine-induced Alzheimer's Disease Rat Model.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026450795260413103307},
pmid = {42136282},
issn = {1875-5739},
abstract = {INTRODUCTION: Nanoemulsions are increasingly recognized as effective carriers for delivering neuroprotective agents in the management of neurodegenerative conditions like Alzheimer's disease. Alzheimer's Disease (AD) is a chronic and progressive neurological disorder marked by memory impairment, cognitive dysfunction, oxidative damage, and degeneration of neurons. This study focuses on designing and evaluating a nanoemulsion-based drug delivery system combining Resveratrol and Ginkgo biloba to investigate their potential neuroprotective effects in a scopolamine- induced Alzheimer's model in Wistar rats.

METHODS: A total of nine water-in-oil nanoemulsion formulations (F1-F9) were developed using probe sonication and examined for various parameters, including droplet size, zeta potential, polydispersity index (PDI), entrapment efficiency, and in vitro drug release profiles.

RESULTS: Among these, Formulation F2, containing 25 mg of Resveratrol and 25 mg of Ginkgo biloba, showed the most favourable characteristics, including a high entrapment efficiency of 90.13%, maximum drug release of 92.33%, a particle size of 92.83 nm, and a zeta potential of 30.75 mV, suggesting good stability of the formulation. For the in vivo evaluation, rats were divided into six groups: normal control, negative control (scopolamine-treated), standard treatment group (Diazepam 2 mg/kg), and three test groups with different formulations. Behavioural studies using the Y-maze demonstrated that the Test Group 1 (treated with F2 formulation) had significantly improved spontaneous alternation behaviour, indicating enhanced cognitive performance. Biochemical analysis showed reduced malondialdehyde (MDA) levels and increased glutathione (GSH) levels, suggesting potent antioxidant activity. Additionally, histopathological examination of brain tissue revealed that the F2-treated group showed reduced neuronal damage and better preservation of hippocampal structure.

DISCUSSION: In rats treated with scopolamine, the optimized F2 nanoemulsion showed excellent physicochemical stability and markedly enhanced cognitive function. Strong antioxidant and neuroprotective effects of the combination formulation are indicated by decreased MDA levels, increased GSH levels, and intact hippocampus architecture.

CONCLUSION: The Resveratrol-Ginkgo biloba nanoemulsion (F2) successfully reduced oxidative stress and cognitive impairment, indicating its potential as a treatment for early-stage Alzheimer's disease. Additional research is needed to confirm its therapeutic application.},
}

@article {pmid42136286,
year = {2026},
author = {Tiwari, P and Kadiri, SK and Sulakhiya, K},
title = {Hyperprolactinemia and Tau Pathology: Unravelling Neuroendocrine Dysregulation for Therapeutic Targeting.},
journal = {Current neurovascular research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672026467094260417052012},
pmid = {42136286},
issn = {1875-5739},
abstract = {BACKGROUND: Hyperprolactinemia, characterized by persistently elevated serum prolactin levels, is traditionally associated with reproductive and metabolic disturbances. Emerging evidence now implicates hyperprolactinemia in central nervous system dysfunction, particularly in the pathogenesis of neurodegenerative disorders. Chronic elevation of prolactin has been linked to tau pathology, a hallmark of Alzheimer's disease and related tauopathies, through mechanisms that promote tau hyperphosphorylation, microtubule destabilization, and neuronal compromise.

METHODOLOGY: This systematic review assesses the evidence on hyperprolactinemia and tau pathology. The overall literature search was performed in PubMed, Scopus, and Web of Science with the help of certain keywords that included prolactin, tau protein, neuroinflammation, oxidative stress, and dopaminergic signaling. The studies were narrowed down to a set of pre-established inclusion and exclusion criteria (original research, molecular and clinical data, relevance to neuropsychiatric disorders, non-English articles, reviews, animal studies that did not have a translational relevance). A clear study selection procedure was used, with independent screening and consensus-based resolution. The results generalize molecular, transcriptomic, neuroimaging, and clinical data to assess mechanistic connections and treatment prospects.

RESULTS: Neurons susceptible to tau accumulation under hyperprolactinemic states exhibit altered apoptotic signaling, impaired vesicular trafficking, and mitochondrial dysfunction. These disruptions correlate with increased neuroinflammation and oxidative stress, suggesting a mechanistic link between endocrine imbalance and tau-mediated neurotoxicity. Therapeutic agents such as dopamine agonists, selective kinase inhibitors, and prolactin receptor antagonists have the potential to restore neuroendocrine homeostasis and mitigate tau pathology.

DISCUSSION: The findings underscore hyperprolactinemia as a modifiable risk factor for cognitive decline. The neuroendocrine-tau axis represents a critical interface where hormonal dysregulation may precipitate neurodegenerative cascades. Clinical implications in the manuscript include that prolactin may serve as a biomarker of an early neurodegenerative process and that its role in the treatment approach includes dopamine agonists, prolactin receptor antagonists, and kinase inhibitors. This simplified methodology will ensure the highlights are original and have translational implications beyond mere abstract repetition.

CONCLUSION: Hyperprolactinemia-induced tau dysregulation presents novel opportunities for neuroprotective targeting. By bridging molecular mechanisms with clinical relevance, this review advocates for longitudinal studies to assess cognitive outcomes in hyperprolactinemic individuals. Emphasizing endocrine health may enhance cognitive resilience and inform future strategies for diagnosis, risk stratification, and therapeutic intervention in neurodegenerative diseases.},
}

@article {pmid42136293,
year = {2026},
author = {Ramesh, J and Jayanthi, B and Mohan, VK and Srinivasan, S and Vijayalakshmi, MK and Mohan, M},
title = {Targeted Nanotechnology Approaches to Bypass the Blood-brain Barrier in Neurodegenerative Disorders.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273444679260416064255},
pmid = {42136293},
issn = {1996-3181},
abstract = {Neurodegenerative diseases like Alzheimer's disease (AD), Parkinson's disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease (HD) are a growing health burden across the world because of the progressive loss of brain cells and the ineffective nature of the available treatment. One significant challenge in the treatment of these conditions is the Blood- -Brain Barrier (BBB), a highly selective interface that limits the access of most therapeutic molecules to the central nervous system. Nanotechnology has become an attractive approach to addressing this difficulty, as it enables the delivery of drugs with high accuracy and actively engages in the repair of the BBB. This review provides an overall synthesis of focused nanotechnology solutions aimed at both circumventing and restoring BBB function in neurodegenerative illnesses. It discusses various nanoparticle (NP) platforms such as polymeric, lipid-based, micellar, metallic, and carbon-derived systems in the light of their physicochemical aspects, transport across the BBB, and therapeutic efficacy. Particular emphasis is put on the receptor-mediated transcytosis, neurovascular unit modulations, and the regulation of Wnt, Shh, and Tie-2 signalling pathways, which are BBB integrity pathways. The review incorporates mechanisms of BBB repair in combination with neuroprotective nanotherapies, rather than focusing solely on end repair. This review covers the role of targeted nanotechnology in the future of therapeutic approaches for neurodegenerative diseases. By connecting materials science, molecular neuroscience, and clinical innovation, it demonstrates how next-generation brain-targeted therapies can be developed using targeted nanotechnology.},
}

@article {pmid42136299,
year = {2026},
author = {Xia, B and Wu, S and Yu, W and Lü, Y},
title = {Research Progress on Intervention Strategies Targeting the Gut-Brain Axis in Alzheimer`s Disease.},
journal = {CNS & neurological disorders drug targets},
volume = {},
number = {},
pages = {},
doi = {10.2174/0118715273431295251201140053},
pmid = {42136299},
issn = {1996-3181},
abstract = {As the most common neurodegenerative disease in the world, Alzheimer's Disease (AD) is characterized by a complex pathogenesis and a lack of effective treatments. In recent years, breakthroughs in the Gut-Brain Axis (GBA) theory have provided a new direction for AD intervention. Studies have shown that AD patients commonly exhibit gut dysbiosis, accompanied by decreased Short-Chain Fatty Acid (SCFA) levels, endotoxin leakage, and increased systemic inflammation, which accelerate cognitive decline via neuroinflammation, Aβ deposition, and synaptic dysfunction. Based on this, intervention strategies targeting the GBA have emerged as a focus of research for slowing down the pathological process of AD. In this study, we systematically summarize the mechanisms linking gut microbiota dysbiosis to AD pathology. This includes the roles of metabolites (e.g., SCFA, LPS, and TMAO) in modulating neuroinflammation and Blood-Brain Barrier (BBB) permeability, as well as the critical involvement of vagal nerve pathways in gut-brain signaling. We further explored the potential of probiotics to improve cognitive function by restoring microbial homeostasis, enhancing anti-inflammatory effects, and elevating neurotrophic factor levels; dietary interventions (e.g., the Mediterranean and MIND diets) to reduce AD risk by modulating microbial composition and metabolic activity; and Fecal Microbiota Transplantation (FMT) to reduce Aβ plaque deposition and mitigate neuroinflammation. Despite promising findings, challenges persist, including discrepancies between animal models and human subjects, individual variability in microbiota composition, and an incomplete understanding of underlying mechanisms. In the future, it will be necessary to combine multiple technologies to develop personalized intervention protocols and optimize clinical translation processes, providing a theoretical basis for the precise treatment of AD.},
}

@article {pmid42136342,
year = {2026},
author = {Liu, CW and Shan, ZX and Li, WJ and Qu, QW and Hou, XQ},
title = {Potential Therapeutic Effects and Mechanisms of Estrogen on Diabetes, Alzheimer's Disease,and Their Comorbidity:A Review.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {328-337},
doi = {10.3881/j.issn.1000-503X.16649},
pmid = {42136342},
issn = {1000-503X},
mesh = {Humans ; *Alzheimer Disease/drug therapy/epidemiology ; *Estrogens/therapeutic use ; *Diabetes Mellitus/drug therapy/epidemiology ; Comorbidity ; },
abstract = {Estrogen is a lipid-soluble steroid hormone and one of the most important female sex hormones.It mainly functions by interacting with estrogen receptors,maintaining normal physiological and pathophysiological functions of the body,and playing a crucial role in regulating blood glucose homeostasis,metabolism,and physiological processes associated with brain learning and memory.Recent studies have shown that estrogen has potential therapeutic effects on diabetes,cognitive impairment and other diseases.It will provide new ideas and treatment strategies for diabetes,Alzheimer's disease,and their comorbidity by regulating the activity of estrogen and the interaction with estrogen receptors to modulate related pathological and physiological processes.This article reviews the latest research progress in the relationship between estrogen and these diseases,providing a new perspective and prospect for the prevention and treatment of diabetes,Alzheimer's disease,and their comorbidity.},
}

Humans
*Alzheimer Disease/drug therapy/epidemiology
*Estrogens/therapeutic use
*Diabetes Mellitus/drug therapy/epidemiology
Comorbidity

@article {pmid42136344,
year = {2026},
author = {Zhang, XT and Chen, SS and Liu, YW and Huang, HR and Yu, Y},
title = {Role of Brain Insulin Resistance in the Pathogenesis of Alzheimer's Disease.},
journal = {Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae},
volume = {48},
number = {2},
pages = {347-354},
doi = {10.3881/j.issn.1000-503X.16614},
pmid = {42136344},
issn = {1000-503X},
mesh = {*Alzheimer Disease/metabolism/etiology/physiopathology/pathology ; *Insulin Resistance ; Humans ; *Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is the most common type of dementia,in which brain insulin resistance (BIR) plays a key role.BIR affects the response of brain cells to insulin and is associated with cognitive decline and pathological features of AD.This study explores the role of BIR in the pathogenesis of AD and evaluates potential treatment strategies,aiming to provide new directions for the prevention and treatment of AD.},
}

*Alzheimer Disease/metabolism/etiology/physiopathology/pathology
*Insulin Resistance
Humans
*Brain/metabolism

@article {pmid42136471,
year = {2026},
author = {Sharma, S and Thakur, A and Paliwal, D and Mondal, R and Saini, S and Sahu, R and Kaushik, N and Tiwari, H},
title = {Exploring the Therapeutic Potential of Coumarin Scaffolds in Alzheimer's Disease: A Comprehensive Review.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575443995260406045449},
pmid = {42136471},
issn = {1875-5607},
abstract = {Alzheimer's disease is a progressive and debilitating form of neurological disorder that affects millions of people across the globe. Alzheimer's disease is essentially defined by the presence of cognitive decline, memory impairments, and behavioral symptoms, and it is also defined by pathological hallmarks such as amyloid plaques, Tau protein inclusions, oxidative stress, & neuroinflammation. However, despite the vast progress made in the field of neuroscience and pharmacology, there is no permanent treatment available for Alzheimer's disease, and the existing treatments are only symptomatic in nature. This has led to the search for new innovative therapeutic approaches based on small molecules with multifunctional pharmacological properties. Among different molecules, Coumarin derivatives have been identified as promising therapeutic agents owing to their high structural diversity and potent ability to bind key molecular targets involved in AD pathogenesis. Coumarin derivatives have been found to have strong potential for modulating oxidative stress, inhibitng cholinesterase, reducing neuroinflammation, and interfering with amyloid-beta aggregation. Recent advancements in the synthesis and design of coumarin derivatives have shown that slight modifications in their structure can yieldsubstantial improvements in their efficacy and selectivity in the treatment of Alzheimer's disease. For coumarin derivatives to be used in the treatment of Alzheimer's disease, they need first to be able to cross the blood-brain barrier. To overcome this limitation, scientists have been working to improve lipophilicity, optimize molecular size and polarity, and design prodrugs. This review provides an updated account of the use of coumarin derivatives in the treatment of Alzheimer's disease. It focuses on their neuroprotective and, symptommodifying effects, and their use in dealing with the multifactorial nature of the disease. Moreover, this paper aims to give recent research findings and discuss the structure-activity relationships of these compounds. The knowledge gained from this review is expected to motivate further research endeavors in the development of stronger and more specific AD drugs.},
}

@article {pmid42136472,
year = {2026},
author = {Shrivastava, N and Husain, A and Haider, K},
title = {Substituted Benzofurans as Potent Anticancer Agents: Advances, Molecular Docking, and SAR Studies.},
journal = {Mini reviews in medicinal chemistry},
volume = {},
number = {},
pages = {},
doi = {10.2174/0113895575435772260422071930},
pmid = {42136472},
issn = {1875-5607},
abstract = {Benzofuran, an oxygen-containing fused heterocyclic aromatic compound, occurs naturally as a secondary metabolite from various plant sources like Rutaceae, Asteraceae, Cyperaceae, and Liliaceae. The derivatives of benzofuran possess a wide range of biological activities, including anticancer, anti-inflammatory, antioxidant, antibiotic, analgesic, anti-Alzheimer's, and immunosuppressive effects. Various synthetic methods are currently used to prepare various benzofuran derivatives. Its therapeutic significance is highlighted by the presence of the benzofuran core in several FDA-approved drugs. Due to the development of resistance in existing anticancer therapies, there is an urgent need for novel, effective, and safe therapeutic approaches. Many heterocyclic moieties and their structural hybrids have been explored for their potential biological activity and have attracted considerable attention as anticancer agents. Substituted benzofuran derivatives are emerging as lead candidates to meet the global challenges of cancer and its available treatment. Benzofuran has the chemical formula C8H6O. Structurally, it consists of a fused ring system: a benzene ring fused to a five-membered furan ring (with one oxygen). Both benzene and furan contribute to its aromatic character. Benzofuran heterocycle plays an important role in drug design and drug discovery due to its versatile nature. The current review summarizes the recent progress in the design, development, drug discovery, and pharmacological actions of benzofuran derivatives as anticancer agents; their molecular docking studies; and structure-activity relationships reported over the past five to six years, emphasizing fused heterocyclic analogues and their prospects to develop as lead molecules. A thorough understanding of the structure-activity relationship will provide a valuable framework for novel drug discovery and design.},
}

@article {pmid42137472,
year = {2026},
author = {Al-Karmalawy, AA and Attia, MI and Alnajjar, R and El-Shiekh, RA and Al Khatib, AO and Yousef, TA and Abdel-Sattar, E},
title = {Discovery of Caralluma-derived pregnane glycosides as potent and selective cholinesterase inhibitors: integrated in silico and in vitro evaluation.},
journal = {RSC advances},
volume = {16},
number = {27},
pages = {24903-24915},
pmid = {42137472},
issn = {2046-2069},
abstract = {Alzheimer's disease (AD) is the fourth leading cause of death among elderly people worldwide. It has a complex pathogenesis, making multitarget-directed ligands (MTDLs) a key therapeutic strategy. This study evaluated pregnane glycosides isolated from Caralluma species (Apocynaceae) as potential cholinesterase inhibitors targeting acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) enzymes for AD treatment. In silico molecular docking against AChE (PDB: 4EY7) and BuChE (PDB: 8CGO) identified caratuberside E and awdelioside B as top AChE binders (-11.09 and -11.49 kcal mol[-1], outperforming the cocrystal inhibitor at -9.52 kcal mol[-1]). For BuChE, caratuberside G and penicilloside C showed superior scores (-10.94 and -11.55 kcal mol[-1] vs. -8.89 kcal mol[-1] for the cocrystal). These results were validated by 200 ns molecular dynamics simulations (stable RMSD values) and MM-GBSA binding free-energy calculations, confirming strong interactions and favourable energetics. In vitro assays (using donepezil as reference) demonstrated potent inhibition: caratuberside E was most active against AChE (IC50 = 0.69 ± 0.07 µM), followed by awdelioside B (IC50 = 18.99 ± 0.06 µM); caratuberside G (IC50 = 1.59 ± 0.16 µM) and penicilloside C (IC50 = 12.38 ± 0.51 µM) excelled against BuChE. Collectively, these pregnane glycosides from Caralluma show promise as selective cholinesterase inhibitors and potential MTDLs for AD therapy.},
}

@article {pmid41928210,
year = {2026},
author = {Leelahavarong, P and Prawjaeng, J and Angkab, P and Wongkom, N and Scheltens, P and Srinonprasert, V and Senanarong, V},
title = {Cost-utility analysis of cerebrospinal fluid versus blood biomarkers for early detection of Alzheimer's disease and mild cognitive impairment in Thailand: a modeling study.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41928210},
issn = {1472-6963},
abstract = {OBJECTIVE: To evaluate the cost-utility of cerebrospinal fluid (CSF) and blood-based amyloid beta biomarkers for early detection of Alzheimer’s disease and mild cognitive impairment among older Thai adults at high risk of dementia.

METHODS: We constructed a decision tree with Markov models from a societal perspective, using a 1-year cycle over a lifetime horizon and applying a 3% annual discount. Amyloid beta (Aβ)1–42 was used for CSF, while Aβ40 and Aβ42 were used for blood. Sensitivity and specificity data were primarily derived from Thai patients at Siriraj Hospital, and nonpharmacological treatment efficacy was obtained from the FINGER study. Epidemiological data, transition probabilities, and costs were collected from the literature and Siriraj Hospital; direct nonmedical costs and utility values were also obtained from Siriraj. We calculated lifetime costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs), evaluating cost-effectiveness against THB160,000 (USD4,370) per QALY. Parameter uncertainty was explored via sensitivity analyses. This is non-clinical trail study.

RESULTS: Compared with no testing, the CSF strategy yielded 0.011 additional life-years and 0.019 additional QALYs for an extra cost of THB2,589 (USD71), resulting in an ICER of THB132,961 (USD3,632) per QALY. Blood-based testing provided 0.009 additional life-years and 0.017 QALYs for an extra cost of THB15,467 (USD422), leading to an ICER of THB907,057 (USD24,776) per QALY.

CONCLUSIONS: CSF biomarker testing is cost-effective in Thailand, whereas blood-based biomarkers are not. Reducing the cost of Simoa (the technology used to measure blood biomarkers) by approximately 83% would improve the cost-effectiveness of blood-based biomarkers. Future research should enhance blood biomarker accuracy.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14405-5.},
}

@article {pmid42125963,
year = {2026},
author = {Juday, TR and Holub, A and Mattke, S and Betts, KA and Kitchen, SA and Liu, H and Frech, FH and Khachaturian, AS},
title = {Community-Based Physician Attitudes Related to the Diagnosis and Treatment of Early Alzheimer's Disease in the United States.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261433309},
doi = {10.1177/15333175261433309},
pmid = {42125963},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/diagnosis/therapy ; United States ; Male ; Female ; *Attitude of Health Personnel ; *Neurologists/psychology ; *Cognitive Dysfunction/diagnosis/therapy ; *Physicians, Primary Care/psychology ; Middle Aged ; Early Diagnosis ; },
abstract = {The increasing incidence of Alzheimer's disease (AD) coupled with emerging diagnostics and treatments underscores the need for early detection of AD, yet identifying these individuals remains challenging. This US study sought to examine community-based physician attitudes regarding diagnosis and treatment of early AD (mild cognitive impairment [MCI] due to AD and mild AD). A total of 177 primary care physicians (PCPs) and 147 neurologists recruited through a national physician panel were surveyed about early AD diagnostic and treatment processes, and self-confidence in identifying and managing the condition. Physicians identified patient and family/caregiver involvement as critical in triggering the diagnostic process. Patterns of use of neurocognitive assessments, structural imaging tests, and AD-specific biomarkers varied between PCPs and neurologists. Confidence diagnosing and managing early AD was a concern across specialties, although was greater among PCPs. Programs promoting awareness of early AD symptoms, and emerging technologies and treatments are critical to timely management.},
}

Humans
*Alzheimer Disease/diagnosis/therapy
United States
Male
Female
*Attitude of Health Personnel
*Neurologists/psychology
*Cognitive Dysfunction/diagnosis/therapy
*Physicians, Primary Care/psychology
Middle Aged
Early Diagnosis

@article {pmid42126808,
year = {2026},
author = {Taylor, TL and Tuke, J and Fernandez, EJ and Hazel, SJ},
title = {Group training classes for dogs with canine cognitive dysfunction: effects on sleep, activity, and caregiver burden.},
journal = {GeroScience},
volume = {},
number = {},
pages = {},
pmid = {42126808},
issn = {2509-2723},
abstract = {Canine Cognitive Dysfunction (CCD) is a progressive neurodegenerative condition of ageing dogs, sharing pathological and clinical features with Alzheimer's disease. Despite the growing prevalence of CCD, non-pharmacological interventions for affected companion animals remain underexplored. This study evaluated the effects of structured group training classes on signs of CCD, sleep, daily activity, and caregiver burden. Forty-two dogs (≥ 8 years) with mild to moderate CCD were enrolled in either a scent-based (S; n = 21) or physical structured training (PST; n = 21) program. Each dog completed five consecutive weekly sessions, with outcomes assessed through the Canine Dementia Scale (CADES), accelerometry (FitBark), and validated caregiver burden measures at baseline, treatment, and post-treatment. CCD scores remained stable across all phases, suggesting no measurable cognitive changes. However, a significant interaction between training type and treatment phase was observed for sleep: dogs in the PST group demonstrated improved Fitbark sleep scores over time, while those in the S group declined. Daily activity followed expected bimodal patterns, with scent-trained dogs exhibiting reductions in morning and evening activity peaks. Caregiver burden decreased significantly across time in both groups, and caregivers reported high satisfaction with class participation, citing enhanced confidence and social support. These findings indicate that while structured training did not alter CCD severity scores, PST was associated with a small improvement in sleep, S was associated with reduced activity, and participation in both classes was linked to reduced caregiver burden. Further research is needed to confirm these changes and determine their effect on dog and human wellbeing. Group training classes may represent an accessible, welfare-focused intervention for managing CCD in companion dogs.},
}

@article {pmid42127455,
year = {2026},
author = {Tzieras, I and Manolopoulos, A and Tweedie, D and Luo, W and Maccecchini, M and Egan, JM and Greig, NH and Kapogiannis, D},
title = {A phase 1, safety, tolerability, and pharmacokinetics study of bisnorcymserine, a highly selective inhibitor of butyrylcholinesterase.},
journal = {Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics},
volume = {23},
number = {3},
pages = {e00918},
doi = {10.1016/j.neurot.2026.e00918},
pmid = {42127455},
issn = {1878-7479},
abstract = {Cholinergic deficiency is a hallmark neurotransmitter abnormality in Alzheimer's disease (AD) that has traditionally been addressed with cholinesterase inhibitors. In severe AD, butyrylcholinesterase (BuChE) becomes the dominant cholinesterase, suggesting a potential therapeutic target. (-)-N1,N8-bisnorcymserine tartrate (BNC) is a selective BuChE inhibitor designed to address this unmet need. We conducted a phase I, single-center, randomized, double-blind, placebo-controlled, ascending single oral dose clinical trial to evaluate the safety, tolerability, and pharmacokinetics of BNC in 30 healthy volunteers. There were no adverse events (AEs) grade 2 or above or any serious adverse events (SAEs). Most events were mild and self-limited, the most common being asymptomatic bradycardia and headache. The mean AUClast (SD) was 120.98 h∗ng/mL (74.30) for the 40 mg dose, 148.20 h∗ng/mL (99.43) for the 80 mg dose, and 196.33 h∗ng/mL (91.74) for the 120 mg dose. Accordingly, median tmax (range) and mean Cmax (SD) were 1.8 (1.0-5.0) hr and 13.94 (7.64) ng/mL for the 40 mg dose, 1.8 (1.5-5.0) hr and 18.54 (6.44) ng/mL for the 80 mg dose, and 2 (1.0-4.5) hr and 20.93 (5.00) ng/mL for the 120 mg dose. The mean half-life of BNC ranged from 5.5 to 7 h. BNC was safe and well tolerated when administered as a single oral dose of up to 120 mg. This first-in-human, phase I study permits further investigation of this drug as a potential symptomatic treatment for AD. ClinicalTrials.gov, NCT01747213.},
}

@article {pmid42128444,
year = {2026},
author = {Atri, A and Apostolova, LG and Iwata, A and Wessels, AM and Atkins, A and Lu, M and Ye, W and Ryan, S and Doty, EG},
title = {Clinical Meaningfulness of Donanemab in Early Symptomatic Alzheimer Disease: Data From the Randomized Phase 3 TRAILBLAZER-ALZ 2 Trial.},
journal = {Neurology. Clinical practice},
volume = {16},
number = {3},
pages = {e200621},
doi = {10.1212/CPJ.0000000000200621},
pmid = {42128444},
issn = {2163-0933},
mesh = {Humans ; *Alzheimer Disease/drug therapy ; Aged ; *Cognitive Dysfunction/drug therapy ; Male ; Female ; *Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology ; Aged, 80 and over ; Disease Progression ; Activities of Daily Living ; *Outcome Assessment, Health Care ; },
abstract = {BACKGROUND AND OBJECTIVES: Understanding the meaningfulness of clinical trial outcomes is essential for people living with Alzheimer disease (AD) and their clinicians to make evidence-based shared treatment decisions in real-world clinical care. Donanemab, a monoclonal antibody targeting the insoluble form of β-amyloid found in plaques, significantly slows cognitive and functional decline of AD in participants with mild cognitive impairment (MCI) or mild AD-related dementia. This analysis reviews the efficacy of donanemab across various clinical outcome assessments, using both published data and new complementary analyses to provide context on its potential benefits for patients and caregivers.

METHODS: We present findings from prespecified and post hoc analyses from the TRAILBLAZER-ALZ 2 trial. Clinical outcomes assessed were Integrated AD Rating Scale (iADRS), comprising the 13-item AD Assessment Scale-Cognitive Subscale (ADAS-Cog13) and AD Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL); Clinical Dementia Rating (CDR)-Sum of Boxes (CDR-SB) for clinical severity and individual cognitive and functional domains; CDR-Global for clinical severity stage progression; meaningful within-patient change (MWPC); and ADCS-Activities of Daily Living dependence score.

RESULTS: Donanemab reduced the risk of progression from MCI to mild AD by 33% (hazard ratio [HR] = 0.67; 95% CI 0.52-0.87; p = 0.003) and from mild to moderate AD by 50% (HR = 0.50; 95% CI 0.33-0.78; p = 0.002). In addition, donanemab reduced MWPC risk over 76 weeks by 38% for CDR-SB (HR = 0.62; 95% CI 0.52-0.75; p < 0.001) and 30% for iADRS (HR = 0.70; 95% CI 0.58-0.84; p < 0.001). Donanemab-treated participants exhibited significant slowing of clinical progression across multiple ADAS-Cog13 and ADCS-iADL items and all CDR-SB cognitive and functional domains. Donanemab also slowed progression of dependence least-squares mean change difference, -0.14 [95% CI -0.24 to -0.04; p = 0.007]), representing 23% slowing of progression (95% CI 6.17%-40.32%), and reduced risk of progression to requiring in-home support by 27% (HR = 0.74; 95% CI 0.59-0.91; p = 0.005).

DISCUSSION: These results add to the evidence and further support clinically meaningful donanemab-mediated effects on cognition and function for patients and their caregivers and may aid communication of realistic treatment expectations and informed decision-making.

ClinicalTrials.gov NCT04437511. Submitted: June 17, 2020; First patient enrolled: June 19, 2020. clinicaltrials.gov/study/NCT04437511 EudraCT Number 2020-000077-25. Start date of recruitment: June 19, 2020. clinicaltrialsregister.eu/ctr-search/trial/2020-000077-25/results.},
}

Humans
*Alzheimer Disease/drug therapy
Aged
*Cognitive Dysfunction/drug therapy
Male
Female
*Antibodies, Monoclonal, Humanized/therapeutic use/pharmacology
Aged, 80 and over
Disease Progression
Activities of Daily Living
*Outcome Assessment, Health Care

@article {pmid42129577,
year = {2026},
author = {Stark, M and Wagner, M and Kuhn, E and Roeske, S and Amthauer, H and Bartels, C and Boecker, H and Brosseron, F and Buchert, R and Buerger, K and Daamen, M and Drzezga, A and Düzel, E and Ersözlü, E and Essler, M and Ewers, M and Fliessbach, K and Glanz, W and Hellmann-Regen, J and Incesoy, EI and Janowitz, D and Kafali, K and Kilimann, I and Krause, BJ and Kronmüller, M and Laske, C and Maier, F and Maurer, A and Michely, J and Perneczky, R and Peters, O and Preis, L and Priller, J and Rauchmann, BS and Reimold, M and Rominger, A and Schmid, M and Schneider, A and Sodenkamp, S and Spottke, A and Spruth, EJ and Teipel, S and Wiltfang, J and , and Jessen, F and Kleineidam, L},
title = {Minor neuropsychological deficits and stage 2 of Alzheimer's disease.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71458},
pmid = {42129577},
issn = {1552-5279},
support = {//Gemeinnützige Hertie-Stiftung/ ; BN012//Deutsches Zentrum für Neurodegenerative Erkrankungen/ ; //Life Molecular Imaging/ ; U01AG024904/NH/NIH HHS/United States ; W81XWH-12-2-0012//U.S. Department of Defense/ ; /AG/NIA NIH HHS/United States ; /EB/NIBIB NIH HHS/United States ; //AbbVie/ ; /ALZ/Alzheimer's Association/United States ; //Alzheimer's Drug Discovery Foundation/ ; //Araclon Biotech/ ; //Biogen/ ; //Bristol-Myers Squibb/ ; //CereSpir, Inc./ ; //Cogstate/ ; //Eisai/ ; //Elan Pharmaceuticals, Inc./ ; //Eli Lilly and Company/ ; //EuroImmun Medizinische Labordiagnostika/ ; //F. Hoffmann-La Roche/ ; //Genentech/ ; //Fujirebio/ ; //GE Healthcare/ ; //IXICO Ltd./ ; //Janssen Alzheimer Immunotherapy Research & Development, LLC./ ; //Lumosity/ ; //Lundbeck/ ; //Merck & Co., Inc./ ; //Meso Scale Diagnostics, LLC./ ; //NeuroRx Research/ ; //Neurotrack Technologies/ ; //Novartis Pharmaceuticals Corporation/ ; //Pfizer Inc./ ; //Piramal Imaging/ ; //Servier/ ; //Transition Therapeutics/ ; /CAPMC/CIHR/Canada ; U24 AG072122/AG/NIA NIH HHS/United States ; },
mesh = {Humans ; *Alzheimer Disease/diagnosis/psychology ; Female ; Aged ; Neuropsychological Tests/statistics & numerical data ; Male ; *Cognitive Dysfunction/diagnosis ; Longitudinal Studies ; Biomarkers ; Aged, 80 and over ; },
abstract = {INTRODUCTION: Subtle symptoms, like subjective cognitive decline (SCD) and minor neuropsychological deficits (MNPD), can improve the risk stratification in preclinical Alzheimer´s disease (AD) but their importance is insufficiently elaborated.

METHODS: We pooled data from cognitively normal individuals participating in three longitudinal cohort studies (N = 13,192, 8,359[63.3%] female, mean [SD] age 71.0[8.4]).

RESULTS: Compared to participants without SCD and MNPD (SCD-/MNPD-), SCD-/MNPD+, SCD+/MNPD-, and SCD+/MNPD+ participants had an increased risk for mild cognitive impairment (MCI) and dementia, including in amyloid-positive individuals. Focusing on SCD+/MNPD+ participants triples the positive predictive value of amyloid biomarker testing for the 5-year prediction of MCI and reduces the required samples size for trials in preclinical AD to one fourth, compared to considering all cognitively normal participants regardless of subtle symptoms.

DISCUSSION: SCD and MNPD offer a powerful approach for risk stratification in preclinical AD, which can improve clinical trial designs, risk counseling, and future case identifications for early treatment.},
}

Humans
*Alzheimer Disease/diagnosis/psychology
Female
Aged
Neuropsychological Tests/statistics & numerical data
Male
*Cognitive Dysfunction/diagnosis
Longitudinal Studies
Biomarkers
Aged, 80 and over

@article {pmid42130250,
year = {2026},
author = {Akar, S and Alvur, O and Evyapan, G and Ozdem, B and Porsuk Doru, I},
title = {Escin Attenuates Amyloid Beta 1-42-Induced Oxidative Stress, Apoptosis, and Neuroinflammation in Neuron-Like SH-SY5Y Cells.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70903},
doi = {10.1002/jbt.70903},
pmid = {42130250},
issn = {1099-0461},
support = {TSA-2023-10713//Van Yuzuncu Yıl University Research Fund/ ; },
mesh = {*Amyloid beta-Peptides/toxicity ; Humans ; *Oxidative Stress/drug effects ; *Apoptosis/drug effects ; *Peptide Fragments/toxicity ; Cell Line, Tumor ; *Neurons/metabolism/pathology/drug effects ; *Escin/pharmacology ; Reactive Oxygen Species/metabolism ; *Neuroprotective Agents/pharmacology ; *Neuroinflammatory Diseases/metabolism/pathology/drug therapy ; Cell Survival/drug effects ; Alzheimer Disease/metabolism/drug therapy/pathology ; NF-kappa B/metabolism ; Inflammation/metabolism ; },
abstract = {The pathogenesis of Alzheimer's disease (AD) involves amyloid beta (Aβ)-induced oxidative stress, apoptotic cell death, and neuroinflammation, contributing to neuronal dysfunction. In our study, a differentiation protocol using retinoic acid was applied to SH-SY5Y cells to generate a neuron-like phenotype, and the neuroprotective efficacy of Escin was investigated by inducing Aβ1-42-mediated cytotoxicity. The experimental protocol involved an initial treatment with 2 µM Escin prior to Aβ1-42 application. Cell viability, intracellular reactive oxygen species (ROS), apoptosis, and inflammatory mediator expression (NF-κB, TNF-α, IL-1β) were assessed by MTT assay, flow cytometry with DCFH-DA, flow cytometry with Annexin V-FITC/7-AAD staining, and RT-qPCR, respectively. In our results, Aβ1-42 exposure was found to significantly reduce cell viability and increase ROS production. Additionally, it was observed to enhance apoptotic cell death and increase pro-inflammatory gene expression. Escin pretreatment was found to significantly mitigate these effects by reducing oxidative stress, apoptosis, and NF-κB-mediated inflammatory signaling. Furthermore, galantamine (10 µM), an approved AD treatment agent, was used as a positive control to compare the effects of Escin and confirmed the experimental model by exhibiting protective effects. In conclusion, these findings demonstrate that Escin is a promising neuroprotective agent and warrant further investigation into its potential to mitigate Aβ-related neuronal damage in AD.},
}

*Amyloid beta-Peptides/toxicity
Humans
*Oxidative Stress/drug effects
*Apoptosis/drug effects
*Peptide Fragments/toxicity
Cell Line, Tumor
*Neurons/metabolism/pathology/drug effects
*Escin/pharmacology
Reactive Oxygen Species/metabolism
*Neuroprotective Agents/pharmacology
*Neuroinflammatory Diseases/metabolism/pathology/drug therapy
Cell Survival/drug effects
Alzheimer Disease/metabolism/drug therapy/pathology
NF-kappa B/metabolism
Inflammation/metabolism

@article {pmid42130609,
year = {2026},
author = {Gobbi, S and Silvestri, E and Tonietto, M and Klein, G and van den Heuvel, M and Magon, S},
title = {Functional connectome metrics reveal distinct prognostic subtypes in two Phase 3 gantenerumab trials.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70259},
pmid = {42130609},
issn = {2352-8737},
abstract = {INTRODUCTION: Alzheimer's disease (AD) heterogeneity poses significant challenges for drug development, identification of individuals at risk, and treatment response prediction. Scientists have leveraged graph theory and resting-state functional magnetic resonance imaging (rs-fMRI) to successfully stratify people with AD. Still, the prognostic value of rs-fMRI graph metrics in AD clinical trials remains unclear.

METHODS: We analyzed rs-fMRI from participants in amyloid-lowering clinical trials. Four graph metrics-global efficiency, clustering coefficient, modularity, and shortest path length-were computed and baseline clusters defined using unsupervised k‑means. We investigated the baseline connectome of each cluster to assess the level of network dysfunction and impairment (i.e., loss of global integration, resulting in disrupted communication between brain regions and reduced global efficiency). These clusters were related to a 116-week change in cognition and brain volume using covariate-adjusted mixed-effects models.

RESULTS: Three clusters emerged with distinct functional connectome efficiency, demographic, and AD-related biomarkers profiles. These baseline differences led to significant variations in disease progression. The most impaired‑connectome cluster declined fastest, whereas the most integrated declined slowest.

DISCUSSION: rs-fMRI graph metrics might effectively stratify participants with AD in clinical trials and serve as potential prognostic biomarkers.},
}

@article {pmid42130762,
year = {2026},
author = {Liu, XY and Yan, YZ and Jiang, AJ and Tan, SJ and Fang, YY and Zeng, P},
title = {Integrating network pharmacology and experimental validation strategies to investigate the mechanisms and key flavonoids in medicinal and edible citrus plants against Alzheimer's disease.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1801263},
pmid = {42130762},
issn = {1663-4365},
abstract = {INTRODUCTION: Due to the complexity of the Alzheimer's disease (AD) pathophysiological processes, there is currently a lack of effective therapeutic drugs. The medicinal and edible substances have multiple advantages in treating AD, but their specific components and mechanisms remain unclear. This study aims to investigate the potential mechanisms of flavonoids in medicinal and edible citrus plants in treating AD and their key phytochemicals.

METHODS: We collected flavonoids identified by UHPLC-Q-TOF-MS/MS in citrus plants from the literatures and evaluate their pharmacological and toxicological parameters. We obtained and systematically analyzed the action targets of the flavonoids of citrus plants and screened the targets related to AD key pathophysiological processes and the corresponding phytochemicals. The results of network pharmacological analysis were further validated through molecular docking, GEO database, and BV2 microglial cells.

RESULTS: A total of 51 flavonoids in medicinal and edible citrus plants were identified, which exhibit favorable pharmacological properties and safety profiles. Multiple flavonoid compounds such as isoquercitrin, astragalin, cynaroside, troxerutin and lonicerin serve as potential acetylcholinesterase inhibitors for the symptomatic treatment of AD. The study identified 45 flavonoids in citrus plants that correspond to 304 AD-related targets, which are involved in multiple pathophysiological processes. Quercetin, nobiletin, hesperidin, apigenin, HTMF, tangeretin and hesperetin have been identified as the key flavonoids of citrus plants that regulate the pathogenesis of AD in a multitargeted manner. The flavonoids of citrus plants primarily regulate the core targets AKT1, TNF, IL6, TP53, IL1B, STAT3, INS, JUN, CASP3 and CTNNB1. Targeting ferroptosis is one of the mechanisms by which citrus plants to ameliorate AD. In vitro experiments also demonstrated that hesperidin and naringin alleviated LPS-induced pro-inflammatory activation of BV2 cells.

CONCLUSION: The various citrus plants flavonoids examined in this study exhibit significant potential for clinical translation, particularly in the early prevention and adjuvant treatment of AD.},
}

@article {pmid42131436,
year = {2026},
author = {Gusmão, LA and Metzke, A and Deau, E and Meijer, L and Tedesco, AC and Köster, RW},
title = {Nitrogen-Doped Graphene Quantum Dots Conjugated to Leucettinib-21 Rescue Differentiating Zebrafish Purkinje Cells by Inhibiting Dyrk1A Kinase.},
journal = {ACS applied nano materials},
volume = {9},
number = {18},
pages = {8023-8038},
pmid = {42131436},
issn = {2574-0970},
abstract = {A major challenge in treating neurological diseases is the transport of compounds across the blood-brain barrier. Herein, we report the synthesis and characterization of nitrogen-doped graphene quantum dots (GQDs) that exhibit high tolerance in zebrafish larvae at high concentrations. In contrast to classical semiconductor quantum dots, vascular microinjection of these fluorescent carbon-based nanomaterials results in rapid tissue distribution and efficient neuronal internalization within the brain, highlighting their potential as nanocarriers for central nervous system delivery. Vascular microinjections of these quantum dots conjugated with the high-affinity Dyrk1A kinase inhibitor Leucettinib-21 (LCTB21) at nanomolar concentrations rescued cell-autonomous dendrite deficiencies in cerebellar Purkinje cells overexpressing human Dyrk1a. LCTB21 concentrations were significantly lower than those of the inhibitor alone. Dyrk1A activity is responsible for neurological defects in Down syndrome and acts as a priming kinase for Alzheimer's disease-associated proteins Tau and APP. Thus, efficient nanodelivery of Dyrk1A inhibitors across the blood-brain barrier improves therapeutic options while minimizing the treatment dose and potential side effects.},
}

@article {pmid42133413,
year = {2026},
author = {Berezutsky, MA and Andronova, TA and Belonogova, YV and Durnova, NA},
title = {[Acteoside: neurobiological activity spectrum, potential in the treatment of age-associated neurodegenerative diseases].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {41-47},
doi = {10.17116/jnevro202612604141},
pmid = {42133413},
issn = {1997-7298},
mesh = {Humans ; *Glucosides/therapeutic use/pharmacology ; *Parkinson Disease/drug therapy/metabolism ; *Phenols/therapeutic use/pharmacology ; *Alzheimer Disease/drug therapy/metabolism ; *Neuroprotective Agents/therapeutic use/pharmacology ; Endoplasmic Reticulum Stress/drug effects ; Animals ; Amyloid beta-Peptides/metabolism ; Microglia/drug effects ; *Neurodegenerative Diseases/drug therapy ; Polyphenols ; },
abstract = {Acteoside (verbascoside, kusaginin) is a phenylethanoid glycoside, which is found in more than 200 species of plants and is characterized by a wide range of pharmacological activity. The results of studies on the neurobiological effects of acteoside, which can be used in the treatment of Alzheimer's disease (AD) and Parkinson's disease (PD), were summarized and analyzed. The PubMed, Scopus, Google Scholar, and e-Library databases were searched for the following keywords: «acteoside», «Alzheimer's disease», «Parkinson's disease», «pathological activation of microglia», «neurotrophic effect», «endoplasmic reticulum stress», «protection of neurons from beta-amyloid», «inhibition of tau protein hyperphosphorylation», «death of dopaminergic neurons», «aggregation of α-synuclein», «cognitive and motor impairment». Experimental studies have shown the ability of acteoside to inhibit pathological activation of microglia, exert a neurotrophic effect, inhibit endoplasmic reticulum stress, protect neurons from beta-amyloid, inhibit tau-protein hyperphosphorylation, reduce intracellular Ca[2+] mobilization dysfunction, protect neurons from glutamate-induced neurotoxicity, prevent dopaminergic neuron death, reduce α-synuclein aggregation, and attenuate cognitive and motor impairments. This compound has good prospects for chemical modification, as its structure features several reactive sites. In the future, acteoside may be used as a multi-purpose complex therapy for AD and PD.},
}

Humans
*Glucosides/therapeutic use/pharmacology
*Parkinson Disease/drug therapy/metabolism
*Phenols/therapeutic use/pharmacology
*Alzheimer Disease/drug therapy/metabolism
*Neuroprotective Agents/therapeutic use/pharmacology
Endoplasmic Reticulum Stress/drug effects
Animals
Amyloid beta-Peptides/metabolism
Microglia/drug effects
*Neurodegenerative Diseases/drug therapy
Polyphenols

@article {pmid42133414,
year = {2026},
author = {Shavlovskaya, OA},
title = {[Choline alfoscerate in the treatment of cognitive impairment].},
journal = {Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova},
volume = {126},
number = {4},
pages = {48-55},
doi = {10.17116/jnevro202612604148},
pmid = {42133414},
issn = {1997-7298},
mesh = {Humans ; *Cognitive Dysfunction/drug therapy ; *Glycerylphosphorylcholine/therapeutic use/administration & dosage ; Alzheimer Disease/drug therapy ; Administration, Oral ; Injections, Intramuscular ; },
abstract = {Multiple randomized controlled trials (RCTs), systematic reviews, meta-analyses, and multidisciplinary studies in both hospital and outpatient settings have demonstrated the high efficacy and safety of choline alfoscerate (CA) therapy for patients with mild and moderate cognitive impairment (MCI), amnestic cognitive impairment, predementia cognitive impairment in Alzheimer's disease (AD), elderly individuals, and first-degree relatives of patients with AD as preventive therapy. The Russian CA drug Cereton is available in several formulations, including solutions for intravenous and intramuscular injection, capsules, and an oral solution, enabling individualized treatment approaches. In hospital settings, injection therapy with Cereton is administered for 10 days, followed by an oral course lasting up to 60 days. The duration and dosage of Cereton oral solution and capsules are determined by patient age and clinical condition. The oral solution is approved for use in children from 6 years of age, and the capsules are approved for use in children from 11 years of age, with treatment courses lasting up to 60 days. Cereton therapy consists of two stages: initial intravenous or intramuscular administration, followed by oral administration of capsules or the oral solution. The drug is generally well-tolerated, with adverse events being infrequent and minor.},
}

Humans
*Cognitive Dysfunction/drug therapy
*Glycerylphosphorylcholine/therapeutic use/administration & dosage
Alzheimer Disease/drug therapy
Administration, Oral
Injections, Intramuscular

@article {pmid42133852,
year = {2026},
author = {Juni, JE and Burns, JM and Salat, DH and Hill, D and Tally, S and Martin, JS and Devous, MD and Moriarty, PM},
title = {Treatment of Clinically Diagnosed Alzheimer's Disease by External Counterpulsation A Randomized Clinical Trial.},
journal = {American journal of Alzheimer's disease and other dementias},
volume = {41},
number = {},
pages = {15333175261451918},
doi = {10.1177/15333175261451918},
pmid = {42133852},
issn = {1938-2731},
mesh = {Humans ; *Alzheimer Disease/therapy ; Female ; Male ; Aged ; *Counterpulsation/methods ; Aged, 80 and over ; *Cognitive Dysfunction/therapy ; Treatment Outcome ; Activities of Daily Living ; },
abstract = {ObjectiveTo assess external counterpulsation (ECP) effects on cognitive and functional decline in early AD.MethodsThis 12-month, multicenter, blinded, randomized, sham-controlled trial enrolled 190 patients with early AD (MCI due to AD or mild AD per NIA-AA clinical criteria). Participants received either full-pressure ECP (150-300 mmHg) or sham (25 mmHg): 3-5 weekly one-hour sessions for 35 treatments, then twice-weekly through six months. Assessments occurred at baseline and weeks 6, 12, 18, 24, 36, and 52. Primary endpoints included ADCS-ADL, ADAS-cog-14, and VADAS-cog.ResultsFull-pressure ECP significantly improved ADCS-ADL scores versus sham (mean change 2.57 vs. -0.49; p=0.036) and VADAS-cog scores (9.95 vs. 5.22; p=0.005) at 12-24 weeks. Benefits persisted through 52 weeks despite treatment cessation at 6 months. No serious device-related adverse events occurred.ConclusionsFull-pressure ECP therapy significantly improved cognition and ADL compared to sham treatment in early AD. ECP represents a novel therapeutic approach warranting further investigation.},
}

Humans
*Alzheimer Disease/therapy
Female
Male
Aged
*Counterpulsation/methods
Aged, 80 and over
*Cognitive Dysfunction/therapy
Treatment Outcome
Activities of Daily Living

@article {pmid41918005,
year = {2026},
author = {Singh, S and Sharma, Y and Bhardwaj, P and Kothari, D and Chhikara, A and Gupta, V and Kumar, D and Choudhary, N and Kondaveeti, SB},
title = {Next generation preventive neurology: how artificial intelligence and machine learning are reshaping Alzheimer's disease research.},
journal = {Behavioral and brain functions : BBF},
volume = {22},
number = {1},
pages = {},
pmid = {41918005},
issn = {1744-9081},
abstract = {UNLABELLED: A neurological condition that worsens over time, Alzheimer’s disease (AD) is typified by memory loss, cognitive decline, and functional degradation. Traditional diagnostic techniques such as neuroimaging, cerebrospinal fluid biomarkers, and neuropsychological testing are often intrusive, costly, or insensitive in the early stages. Recent years have seen the emergence of AI and ML as game-changing technologies for AD risk assessment, early detection, and customized prevention. Using sophisticated models such as deep learning, convolutional neural networks (CNNs), and graph-based algorithms, AI-driven methods achieve high performance: CNNs, for example, have reached diagnostic accuracies of 94–99% for early AD and mild cognitive impairment using multimodal MRI and PET data. However, most reported performance metrics are derived from retrospective analyses and internal validation cohorts, with limited external validation across diverse populations. These methods include multimodal data integration from neuroimaging, genetics, and clinical records. Years before symptoms appear, AI-based frameworks can predict disease progression, identify modifiable risk factors, and guide individualized treatment plans. Future developments in federated learning and explainable AI (XAI) are promising, although data privacy, algorithmic bias, and ethical ramifications are concerns. Overall, AI and ML have a great deal of promise to transform the prevention of AD, enabling precision therapy and enhancing the lives of those who are at risk.

GRAPHICAL ABSTRACT: [Image: see text]},
}

@article {pmid42116584,
year = {2026},
author = {Bala, VC and Singh, MK and Kumar, A and Tiwari, SK and Gupta, AK and Chawla, R and Kumar, S},
title = {Targeting α-Synuclein: Current Strategies and Emerging Therapies for Synucleinopathies.},
journal = {Protein and peptide letters},
volume = {33},
number = {1},
pages = {258-274},
doi = {10.2174/0109298665429866260217115717},
pmid = {42116584},
issn = {1875-5305},
mesh = {Humans ; *alpha-Synuclein/metabolism/genetics/antagonists & inhibitors ; *Synucleinopathies/metabolism/therapy/drug therapy/pathology ; *Parkinson Disease/metabolism/therapy/drug therapy/pathology ; Autophagy/drug effects ; Animals ; Oxidative Stress ; },
abstract = {Alpha-synuclein (α-syn) is a crucial protein involved in the pathogenesis of Parkinson's Disease (PD) and other synucleinopathies. It is important with respect to neuron health, regulation of α-syn protein synthesis, and its degradation. Numerous cellular pathways implicated in the process of autophagy, chaperone, and proteolysis play a vital role in the maintenance of α-syn protein homeostasis. Autophagy dysfunction defeats α-syn protein accumulation and neuroinflammation, as present in dementia with Lewy bodies and sporadic PD. Oxidative stress is another key factor that intensifies α-syn protein misfolding and aggregation, thereby leading to neurodegeneration. Involvement in the treatment of α-syn related disorders includes passive and active immunization, inhibitors of protein aggregation, gene silencing technology, modulators of synaptic function, and target drug delivery systems. Other α-syn related therapy approaches include the development of a novel herbal formulation focusing on the gut-brain axis and interventions designed to enhance protein quality control. As clinical trials move forward, minimizing challenges related to the target involved, biomarkers, and patient stratification is crucial to decoding these therapies into effective management. These insights not only advance our understanding of α-syn biology but also highlight the urgency of early and multi-targeted therapeutic interventions.},
}

Humans
*alpha-Synuclein/metabolism/genetics/antagonists & inhibitors
*Synucleinopathies/metabolism/therapy/drug therapy/pathology
*Parkinson Disease/metabolism/therapy/drug therapy/pathology
Autophagy/drug effects
Animals
Oxidative Stress

@article {pmid42116599,
year = {2026},
author = {Saha, T and Vats, T and Mehan, S},
title = {Rituximab Beyond Oncology: Targeting B-Cell-Mediated Immunomodulatory Therapy in Neurodegenerative and Neuropsychiatric Disorders.},
journal = {Immunopharmacology and immunotoxicology},
volume = {},
number = {},
pages = {1-77},
doi = {10.1080/08923973.2026.2671714},
pmid = {42116599},
issn = {1532-2513},
abstract = {Neurological and neuropsychiatric disorders, including multiple sclerosis (MS), Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune encephalitis (AE), represent a growing global health burden due to their multifaceted pathophysiology and limited treatment options. These disorders are characterized by neuroinflammation, oxidative stress, protein aggregation, and blood-brain barrier (BBB) disruption, which contribute to neuronal damage and progressive functional decline. Emerging evidence underscores the pivotal role of B cells in driving disease progression through antibody production, antigen presentation, and cytokine release. Rituximab, a chimeric monoclonal antibody targeting CD20 on B cells, has shown promise as a potential immunomodulatory therapy for these conditions. Rituximab mediates its therapeutic effects via mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and induction of apoptosis. In MS, rituximab reduces pro-inflammatory cytokines, demyelination, and immune cell activity, thereby delaying disease progression. Preclinical studies suggest its neuroprotective potential in AD and PD by mitigating B-cell-mediated neuroinflammation and oxidative stress. Furthermore, rituximab demonstrates efficacy in AE, NMOSD, and MOGAD by depleting pathogenic B cells and reducing relapse rates. Despite its proven efficacy, rituximab poses risks such as hypogammaglobulinemia, infection, and infusion-related reactions, necessitating careful patient selection, continued monitoring, and optimization of dosing regimens. This review highlights rituximab's immunomodulatory mechanisms and its expanding role in neurodegenerative and neuropsychiatric disorders. While ongoing clinical trials explore its efficacy in ALS, depression, and schizophrenia, future research should focus on identifying biomarkers of treatment response, improving CNS penetration, and combining rituximab with other therapies to enhance safety and therapeutic outcomes. Rituximab's ability to target B-cell-driven pathology positions it as a promising agent in the evolving landscape of neuroimmunology.},
}

@article {pmid42116632,
year = {2026},
author = {Han, KJ and Lv, YX and Xie, D and Zou, LH and Jiang, Q and Xie, SD and Zhang, YJ and Zhao, P and Yang, XQ and Wee, SK},
title = {Molecular Mechanistic Studies on Caffeoylquinic Acid Derivatives From Vaccinium dunalianum Wight as Dual-Target Inhibitors of AChE and BChE With In Vitro Inhibitory Evaluation and Molecular Docking.},
journal = {Chemistry & biodiversity},
volume = {23},
number = {5},
pages = {e03013},
doi = {10.1002/cbdv.202503013},
pmid = {42116632},
issn = {1612-1880},
support = {202205AC160049//Young and Middle-Aged Academic and Technological Leaders of Yunnan Province/ ; 22267018//National Natural Science Foundation of China/ ; 32060327//National Natural Science Foundation of China/ ; 202501BD070001-027//Yunnan Fundamental Research Projects/ ; 202401AT070295//Yunnan Fundamental Research Projects/ ; 202503AC100002//Yunnan Fundamental Research Projects/ ; 202505AO120060//Yunnan Foreign Expert Program/ ; },
mesh = {*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification ; *Molecular Docking Simulation ; *Quinic Acid/analogs & derivatives/pharmacology/chemistry/isolation & purification ; *Acetylcholinesterase/metabolism ; *Butyrylcholinesterase/metabolism ; Animals ; Rats ; Structure-Activity Relationship ; PC12 Cells ; Plant Leaves/chemistry/metabolism ; Humans ; Dose-Response Relationship, Drug ; Molecular Structure ; Plant Extracts/chemistry/pharmacology ; Cell Survival/drug effects ; },
abstract = {Alzheimer's disease (AD) involves impaired cholinergic neurotransmission, so inhibiting acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is a major treatment strategy. Vaccinium dunalianum Wight leaf extracts, abundant in caffeoylquinic acids (CQAs), potently inhibit AChE (IC50 = 0.12 ± 0.01 mg/mL) and BChE (IC50 = 0.01 ± 0.01 mg/mL). Key bioactive compounds include 1-O-caffeoylquinic acid (1-CQA), chlorogenic acid (CGA), neochlorogenic acid (NCGA), and cryptochlorogenic acid (CCGA). All inhibited both enzymes concentration-dependently; 1-CQA was strongest (AChE IC50 = 0.25 ± 0.03 µM; BChE IC50 = 0.10 ± 0.01 µM), surpassing galantamine. Kinetics and docking showed reversible mixed-type inhibition targeting AChE catalytic and peripheral sites. Fluorescence quenching affirmed high-affinity binding, strongest for 1-CQA. It also showed low cytotoxicity in PC12 cells (≤10 µM). These findings reveal a dual cholinesterase inhibitory mechanism and support CQAs as promising anti-AD agents.},
}

*Cholinesterase Inhibitors/chemistry/pharmacology/isolation & purification
*Molecular Docking Simulation
*Quinic Acid/analogs & derivatives/pharmacology/chemistry/isolation & purification
*Acetylcholinesterase/metabolism
*Butyrylcholinesterase/metabolism
Animals
Rats
Structure-Activity Relationship
PC12 Cells
Plant Leaves/chemistry/metabolism
Humans
Dose-Response Relationship, Drug
Molecular Structure
Plant Extracts/chemistry/pharmacology
Cell Survival/drug effects

@article {pmid42118381,
year = {2026},
author = {S, K and L, G and S, PP and C, K},
title = {Aspirin as a neuroprotective scaffold in Alzheimer's disease: inflammation, oxidative stress, and future directions.},
journal = {Molecular biology reports},
volume = {53},
number = {1},
pages = {},
pmid = {42118381},
issn = {1573-4978},
mesh = {*Alzheimer Disease/drug therapy/metabolism ; Oxidative Stress/drug effects ; *Aspirin/pharmacology/therapeutic use ; Humans ; *Neuroprotective Agents/pharmacology/therapeutic use ; Inflammation/drug therapy/metabolism ; Animals ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use ; Neuroinflammatory Diseases/drug therapy ; Cyclooxygenase Inhibitors/pharmacology ; },
abstract = {Alzheimer's disease (AD) is one of the most common forms of dementia. AD is associated with memory loss and cognitive decline. Several research works have been carried out to treat AD. However, currently available treatment options are only useful in the treatment of the individual pathology of AD but not useful in disease modification. Recent research works have identified the associated effects of neuroinflammation, oxidative stress, and glial cell dysfunction in AD pathology. Aspirin is one of the most commonly used NSAIDs in the treatment of several inflammatory diseases. Aspirin inhibits cyclooxygenase (COX) enzymes through an irreversible pathway. However, aspirin also exhibits other important pharmacological properties. This review aims to highlight the potential of aspirin-based multi-target directed ligands in the regulation of AD pathology through the regulation of neuroinflammation and oxidative stress.},
}

*Alzheimer Disease/drug therapy/metabolism
Oxidative Stress/drug effects
*Aspirin/pharmacology/therapeutic use
Humans
*Neuroprotective Agents/pharmacology/therapeutic use
Inflammation/drug therapy/metabolism
Animals
Anti-Inflammatory Agents, Non-Steroidal/pharmacology/therapeutic use
Neuroinflammatory Diseases/drug therapy
Cyclooxygenase Inhibitors/pharmacology

@article {pmid42118396,
year = {2026},
author = {Kumar, R and Patel, S and Mishra, PS and Srivastava, S and Sridhar, SB and Shareef, J and Sahu, R and Tariq, M and Uddin, J and Muhsinah, AB},
title = {From Molecular Networks to Medicines: Targeting Complexity in Alzheimer's Disease (AD) Therapy.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42118396},
issn = {1559-1182},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; Animals ; *Molecular Targeted Therapy/methods ; Amyloid beta-Peptides/metabolism ; },
abstract = {Alzheimer's disease (AD) is a multidimensional neurodegenerative disease leading to progressive loss of cognitive function and a growing health burden on the world population. Although decades of research have been conducted on this disease, current therapies have limited clinical value, mainly because researchers have not fully incorporated the intricate molecular pathways underlying its development and progression. This review summarizes current knowledge of AD pathophysiology, including amyloid beta (Aβ) dysregulation, tau hyperphosphorylation, neuroinflammation, mitochondrial dysfunction, oxidative stress, and synaptic breakdown. Although the amyloid- and tau-centered paradigms remain prevailing in the field, we note newer molecular targets, including secretase modulators, inflammatory signaling hubs, mitotic and autophagic regulators, epigenetics, and synaptogenesis pathways. We prioritize mechanistic, structural, cellular, and systems levels to facilitate a rational development of therapeutic understanding. The latest trends in medicinal chemistry and computational drug design, multi-target- directed ligands and hybrid scaffolds, as well as in silico ADMET optimization, are also discussed. Furthermore, we discuss the therapeutic aspects of bioinspired analogues of natural products. Lastly, we discuss the ongoing clinical development initiatives, opportunities, and major translational issues. In general, we highlight the need for integrative, mechanism-oriented, and personalized treatment approaches to propel the next generation of AD therapies.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
Animals
*Molecular Targeted Therapy/methods
Amyloid beta-Peptides/metabolism

@article {pmid42121268,
year = {2026},
author = {Cho, IH and Putra, HM and Jung, CW and Hyun, GH and Jang, HH and Hwang, IG and Kwon, SW},
title = {Neuroprotective effects of quercetin in animal models of neurodegenerative diseases: A systematic review and meta-analysis.},
journal = {Journal of the science of food and agriculture},
volume = {},
number = {},
pages = {},
doi = {10.1002/jsfa.70699},
pmid = {42121268},
issn = {1097-0010},
support = {RS-2022-RD010385//Rural Development Administration/ ; },
abstract = {Neurodegenerative conditions such as Alzheimer's disease and Parkinson's disease are characterized by progressive neuronal loss driven by oxidative stress and inflammation. Quercetin, a dietary flavonoid with established antioxidant and anti-inflammatory properties, has emerged as a potential neuroprotective agent. This study aimed to quantitatively synthesize and evaluate preclinical evidence regarding the impact of quercetin on neurodegenerative biomarkers and cognitive performance. A comprehensive literature search was conducted using PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials (CENTRAL). After strict screening and selection, 19 studies were included. These evaluated the effects of quercetin on: Morris water maze (MWM) performance; inflammatory cytokines - including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-10 (IL-10); the oxidative stress marker malondialdehyde (MDA); antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH); brain-derived neurotrophic factor (BDNF); and acetylcholinesterase (AChE) activity. Subgroup analyses based on quercetin dose (<100 mg kg[-1] versus ≥100 mg kg[-1]) and treatment duration (<28 versus ≥28 days) were performed. Quercetin improved cognitive performance significantly by reducing escape latency and improving performance on memory retention indicators. It decreased pro-inflammatory cytokines (IL-6 and TNF-α), increased IL-10, enhanced antioxidant enzyme activity (CAT, SOD, and GSH), reduced MDA levels, up-regulated BDNF, and inhibited AChE. Subgroup analyses suggested that quercetin exerted stronger effects at lower doses and with longer treatment durations, although not all subgroup differences were statistically significant. Quercetin demonstrated multi-targeted neuroprotective effects in animal models, improving cognition and modulating inflammatory, oxidative, and neurotrophic pathways. These findings support the potential of quercetin as a therapeutic agent for neurodegenerative diseases, warranting further clinical investigation. © 2026 The Author(s). Journal of the Science of Food and Agriculture published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.},
}

@article {pmid42123478,
year = {2026},
author = {Xiao, Y and Huang, W and Chen, L and Huang, R and Guo, Y and Liu, W and Wang, X and Wang, J and Bao, J and Shu, X},
title = {Amyloid Precursor Protein Abnormalities Destabilize Membrane Ferroportin: A Novel Mechanism Underlying Early Brain Pathologies and Memory Impairment in Alzheimer's Disease.},
journal = {International journal of molecular sciences},
volume = {27},
number = {9},
pages = {},
doi = {10.3390/ijms27093892},
pmid = {42123478},
issn = {1422-0067},
support = {82371195//National Natural Science Foundation of China/ ; 82001281//National Natural Science Foundation of China/ ; No. 2024HBQZYCSB046//Intelligent Cancer Prevention and Control Platform Development and Industrialization/ ; },
mesh = {*Alzheimer Disease/metabolism/pathology/genetics ; Animals ; Ferroportin ; *Amyloid beta-Protein Precursor/metabolism/genetics ; *Cation Transport Proteins/metabolism/genetics ; Mice ; Humans ; *Memory Disorders/metabolism/pathology ; *Brain/pathology/metabolism ; Mice, Transgenic ; Ferroptosis ; Disease Models, Animal ; Amyloid beta-Peptides/metabolism ; Mutation ; Oxidative Stress ; },
abstract = {Alzheimer's disease (AD) research has primarily focused on amyloid beta (Aβ) and tau protein; however, drug development targeting these two proteins has been disappointing. Therefore, there is an urgent need to explore the novel pathogenic mechanisms underlying AD. Recently, we found that expression of the K670N/M671L-mutated amyloid precursor protein (APP) in 293T cells significantly reduced membrane ferroportin (FPN) levels. Furthermore, 2-month-old APP/PS1 mice exhibited a marked decrease in membrane FPN levels, while total FPN expression and Aβ levels remained unchanged. Further studies revealed that features of ferroptosis were present in the brains of 2-month-old APP/PS1 mice, and that treatment with ferroptosis inhibitors or iron chelation significantly alleviated early pathological changes and cognitive impairment in these animals. In addition, supplementation with an APP-FPN binding peptide during the early phase ameliorated AD-related pathologies, including Aβ deposition, neuroinflammation, oxidative stress, and synapse-associated protein deficits, in APP/PS1 mice. Collectively, our findings suggest that APP mutations may contribute to early brain pathological changes and subsequent memory impairment in AD by downregulating membrane trafficking of FPN and inducing ferroptosis, thereby providing new molecular targets for drug development.},
}

*Alzheimer Disease/metabolism/pathology/genetics
Animals
Ferroportin
*Amyloid beta-Protein Precursor/metabolism/genetics
*Cation Transport Proteins/metabolism/genetics
Mice
Humans
*Memory Disorders/metabolism/pathology
*Brain/pathology/metabolism
Mice, Transgenic
Ferroptosis
Disease Models, Animal
Amyloid beta-Peptides/metabolism
Mutation
Oxidative Stress

@article {pmid42125083,
year = {2026},
author = {Zhao, C and Peng, X and Cheng, Z and Yue, S and Wang, Z and Ma, L and Li, J and Shang, M},
title = {Light-based 40 Hz sensory therapy for brain disorders: physiological basis, therapeutic mechanisms, and future prospects.},
journal = {Frontiers in medicine},
volume = {13},
number = {},
pages = {1730333},
pmid = {42125083},
issn = {2296-858X},
abstract = {In recent years, 40 Hz flickering light and/or sound therapy has been confirmed to have certain therapeutic effects on Alzheimer's disease (AD), although the underlying mechanisms remain unclear. This approach has been widely explored for the treatment of various neurological disorders, but its efficacy must be verified. The induction of gamma oscillations in the brain by 40 Hz flickering light and/or sound stimulation is likely a critical component underlying its therapeutic effects across brain diseases. Elucidating the physiological basis and mechanisms by which such stimuli induce gamma oscillations may reveal its mechanisms of action in treating diseases. Although 40 Hz flickering light and/or sound intervention offers certain advantages in improving neurological function, challenges related to technical optimization and clinical promotion must be addressed. Therefore, in this paper, the underlying mechanisms through which 40 Hz flickering light and/or sound intervention induces gamma oscillations, including both neuronal and non-neuronal mechanisms, are explained. The clinical therapeutic outcomes of 40 Hz flickering light and/or sound intervention for various neurodegenerative diseases are subsequently examined, and the mechanisms underlying are summarized. Furthermore, the limitations of this therapy and corresponding improvement measures are discussed, providing a theoretical reference for further refining this technology and expanding its clinical applications. Finally, future development directions are provided, with the aims of advancing related research and facilitating the application of this therapy in the treatment of brain diseases.},
}

@article {pmid42111521,
year = {2026},
author = {Guo, B and Wang, J and Lou, F and Yuan, B and Chen, Z and Tang, C and Chen, W and Yi, F and Jiang, J and Hu, G and Cong, C and Lu, Y},
title = {Graphene field-effect transistor based multiplexed sensing platform for simultaneous detection of multiple Alzheimer's disease biomarkers.},
journal = {RSC advances},
volume = {16},
number = {26},
pages = {23937-23944},
pmid = {42111521},
issn = {2046-2069},
abstract = {Simultaneous detection of multiple biomarkers for one disease using a single drop of body fluid is challenging yet critical to confirm symptoms in the early stage. This study presents the development of a graphene field-effect transistor (GFET)-based multiplexed sensing platform designed for overcoming this obstacle. The platform utilizes a hexamethyldisilazane (HMDS) blocking layer as a hydrophobic treatment to enable recognition element (probe/aptamer) modifications within a small chip area (3 × 3 mm[2]), and this further enables simultaneous detection of multiple targets (multi-targets) in complex biological samples. The optimized aptamer/probe functionalization also enhances the specificity, sensitivity, and accuracy of the sensor. The technology was demonstrated with Alzheimer's disease (AD) biomarkers as a case study. Two distinctive biomarkers, hsa-miR-125b and Aβ42, are detected simultaneously with distinguishable signatures, and the lowest tested concentration is 1 fM. The cross-check experiments also show the effectiveness of the multi-target detection capability. This concise platform paves the way for accurate detection of early-stage diseases when the simultaneous identification of multiple biomarkers is required.},
}

@article {pmid42111940,
year = {2026},
author = {Ismail Al-Khaleel, R and Kalenahalli, Y and Hemalatha, S and Baker, S and Raj, SN and Rangappa, KS and Gowda, S and Siddaiah, C},
title = {Metabolomic analysis of Pennisetum glaucum seed extracts using advanced LC-MS/MS and Q-TOF technology.},
journal = {Journal of food science and technology},
volume = {63},
number = {5},
pages = {962-970},
pmid = {42111940},
issn = {0022-1155},
abstract = {UNLABELLED: Pearl millet (Pennisetum glaucum) is a cereal widely cultivated and grown in Africa and the Indian subcontinent for centuries. The present investigation aims to use LC-MS/MS to analyze the secondary metabolites present in pearl millet seeds using different solvents such as methanol, hexane, chloroform, and ethyl acetate. METLIN software was used to identify the metabolites. The analysis revealed the presence of 650 metabolites, among which 145 were commonly found in all the solvent extracts. The major classes of identified metabolites are terpenoids, flavonoids, sterols, amino acids, fatty acids, glycoconjugates, and carbohydrates. 80% methanolic extract and ethyl acetate extract yielded the highest concentrations of terpenoid (23%) and flavonoid (17%). The enrichment analysis was performed to statistically examine and identify the metabolites present in the metabolomic library dataset. In the hexane extract, notable metabolites such as quercetin and rutin were identified, which possess potential for the management of Alzheimer's disease due to their neuroprotective effects (p < 4e-35). In the methanol extract, metabolites like gallic acid and caffeic acid were associated with uremia treatment due to their antioxidant activity (p < 5e-37). Overall, the present study provides an overview of the metabolites present in the pearl millet seeds and the nutritive as well as therapeutic potential of these millets in the management of human diseases.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13197-025-06328-6.},
}

@article {pmid42112453,
year = {2025},
author = {Usman, M and Ashebir, S and Okey-Mbata, C and Yun, Y and Kim, S},
title = {Neuroengineering Frontiers: A Selective Review of Neural Interfaces, Brain-Machine Interactions, and Artificial Intelligence in Neurodegenerative Diseases.},
journal = {Applied sciences (Basel, Switzerland)},
volume = {15},
number = {21},
pages = {},
pmid = {42112453},
issn = {2076-3417},
support = {SC1 NS122448/NS/NINDS NIH HHS/United States ; UG3 EB036466/EB/NIBIB NIH HHS/United States ; },
abstract = {Neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD), present a growing public health challenge globally. Recent advancements in neurotechnology and neuroengineering have significantly enhanced brain-computer interfaces, artificial intelligence, and organoid technologies, making them pivotal instruments for diagnosis, monitoring, disease modeling, treatment development, and rehabilitation of various diseases. Nonetheless, the majority of neural interface platforms focus on unidirectional control paradigms, neglecting the need for co-adaptive systems where both the human user and the interface continually learn and adapt. This selected review consolidates information from neuroscience, artificial intelligence, and organoid engineering to identify the conceptual underpinnings of co-adaptive and symbiotic human-machine interaction. We emphasize significant shortcomings in the advancement of long-term AI-facilitated co-adaptation, which permits individualized diagnostics and progression tracking in Alzheimer's disease and Parkinson's disease. We concentrate on incorporating deep learning for adaptive decoding, reinforcement learning for bidirectional feedback, and hybrid organoid-brain-computer interface platforms to mimic disease dynamics and expedite therapy discoveries. This study outlines the trends and limitations of the topics at hand, proposing a research framework for next-generation AI-enhanced neural interfaces targeting neurodegenerative diseases and neurological disorders that are both technologically sophisticated and clinically viable, while adhering to ethical standards.},
}

@article {pmid42113681,
year = {2026},
author = {Wang, S and Yuan, X and Wang, T and Yang, M and Dong, P and Han, H},
title = {Mechanisms and Therapeutic Targeting of the GutMicrobiota-Immune-Brain Axis in Alzheimer's Disease.},
journal = {Immunological investigations},
volume = {},
number = {},
pages = {1-31},
doi = {10.1080/08820139.2026.2669375},
pmid = {42113681},
issn = {1532-4311},
abstract = {BACKGROUND: Alzheimer's disease (AD) is a highly prevalent neurodegenerative disease globally. The main pathological features of AD are amyloid-β (Aβ) deposition and tau hyperphosphorylation. Recent studies suggest that the gut microbiota-immunity-brain axis plays an important role in the onset and progression of AD. Gut microbiota dysbiosis may impair intestinal barrier integrity and promote the entry of pro-inflammatory mediators into the circulation. Pro-inflammatory signals in the bloodstream may further activate the central immune system, drive microglial polarization, and increase the release of inflammatory factors in the brain. The resulting neuroinflammatory cascade may aggravate Aβ accumulation, tau phosphorylation, and cognitive impairment, although this mechanism has not been conclusively established in humans.

METHODS AND RESULTS: Based on relevant literature on AD, gut microbiota, immunity, neuroinflammation, and the gut-brain axis, this article systematically reviews the mechanism of action of the microbiota-immunity-brain axis in AD. Current intervention strategies targeting this axis, including probiotics, fecal microbiota transplantation, dietary interventions, and traditional Chinese medicine, were also discussed. Such intervention measures have the potential to regulate the balance of the gut microbiota, reduce neuroinflammation, and slow the progression of AD pathology.

CONCLUSION: It is essential to integrate multi-omics approaches in future research to deepen the understanding of AD pathogenesis and support the development of more precise and personalized treatment strategies.},
}

@article {pmid42115432,
year = {2026},
author = {Ferré, CG and Pallàs, M and Franco, R},
title = {Molecular and statistical weaknesses of the p-tau217/Aβ1-42 plasma ratio for alzheimer's diagnosis.},
journal = {Journal of molecular medicine (Berlin, Germany)},
volume = {104},
number = {1},
pages = {},
pmid = {42115432},
issn = {1432-1440},
mesh = {Humans ; *Alzheimer Disease/diagnosis/blood ; *Amyloid beta-Peptides/blood ; *tau Proteins/blood ; *Biomarkers/blood ; *Peptide Fragments/blood ; Reproducibility of Results ; },
abstract = {The FDA's approval of the Lumipulse G p-tau217/Aβ1-42 plasma ratio enhances access to Alzheimer's diagnostics but risks confusing convenience with biological accuracy. The assay is scalable and non-invasive, yet it relies on a ratio of two markers that are unstable and only partly specific to the disease, raising concerns about reproducibility and interpretation. The reported performance is solid in carefully selected groups, but is likely to be less robust in broader real-world populations with lower disease prevalence, mixed pathologies, and higher comorbidity. If biomarker-based enrollment is shaped by imperfect specificity, misclassification may propagate into trial recruitment, treatment-effect estimates, and downstream validation. This concern is amplified when biomarkers are validated within partially circular frameworks in which plasma assays, positron emission tomography, cerebrospinal fluid markers, and clinical diagnosis reinforce one another without fully independent neuropathological confirmation. Blood-based assays remain promising, but their clinical use should be guided by rigorous analytical scrutiny, broad validation across diverse populations, standardized pre-analytical handling, and transparent data sharing. The aim of biomarker science should be not striking receiver operating characteristic curves in curated cohorts, but biological fidelity across human heterogeneity and validation grounded in mechanism. Until then, the p-tau217/Aβ1-42 ratio is best regarded as a useful contextual or research tool rather than a standalone diagnostic benchmark, so that precision medicine does not rest on associations whose causal and mechanistic basis remains insufficiently established. Its most appropriate use may be in longitudinal monitoring within the same individual, where changes over time may be more informative than a single threshold-based diagnostic result.},
}

Humans
*Alzheimer Disease/diagnosis/blood
*Amyloid beta-Peptides/blood
*tau Proteins/blood
*Biomarkers/blood
*Peptide Fragments/blood
Reproducibility of Results

@article {pmid42115835,
year = {2026},
author = {Fu, Q and Yin, X and Xu, S},
title = {Disentangling treatment status from disease severity in studies of diabetes and Alzheimer's disease biomarkers.},
journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association},
volume = {22},
number = {5},
pages = {e71465},
doi = {10.1002/alz.71465},
pmid = {42115835},
issn = {1552-5279},
support = {824774630//National Natural Science Foundation of China/ ; 82274643//National Natural Science Foundation of China/ ; 20234Y0023//Shanghai Municipal Health Commission/ ; },
}

@article {pmid42116113,
year = {2026},
author = {Li, Y and Hu, C and Xia, C and Wang, X and Zhou, X and Xu, R and Li, Y and Mo, F and Zhao, B and Xu, L and Zhu, C and Chen, Z},
title = {A novel nasal mucosal peptide-modified co-delivery system for ginsenoside Rg1, Rb1, and notoginseng saponin R1 in the amelioration of AD.},
journal = {Journal of nanobiotechnology},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12951-026-04532-w},
pmid = {42116113},
issn = {1477-3155},
support = {202510315035//National Innovation and Entrepreneurship Training Program for Undergraduate/ ; 82304729//National Natural Science Foundation of China/ ; 82574587//National Natural Science Foundation of China/ ; BK20230457//Natural Science Foundation of Jiangsu Province/ ; ZYXYL2024-005//Scientific Research Foundation of Nanjing University of Chinese Medicine/ ; },
abstract = {The drug delivery for Alzheimer's disease (AD) faces substantial obstacles owing to the presence of the blood-brain barrier (BBB). This circumstance highlights the nose-brain route as pivotal for enhancing drug distribution to the brain. As the efficiency of brain entry is constrained by the physiological barrier of the nasal cavity, the development of strategies to efficiently traverse this barrier is imperative for enhancing the effectiveness of AD treatment. In the present study, a cell-penetrating peptide (CPPs) named LK4, which originates from mastoparan-L (MPL), was employed. Its capacity to efficiently penetrate the physiological barrier of the nasal cavity was demonstrated. LK4 was modified into polydopamine (PDA) nanoparticles to construct nanoparticles containing ginsenoside Rg1, ginsenoside Rb1, and notoginseng saponin R1 (TGS), designated as LK4-TGS-PDA. Experiment results reveal that the LK4-TGS-PDA drug delivery system can enhance the uptake of olfactory neurons and promote epithelial transport. In an in vitro nasal mucosal barrier model, LK4 modification increased the apparent permeability coefficients of R1, Rg1, and Rb1 by 1.2-, 1.2-, and 12-fold, respectively, compared to unmodified nanoparticles. Following nasal administration, the brain concentrations of R1, Rg1, and Rb1 increased by 19-fold, 30-fold, and 15-fold, respectively, and the relative brain bioavailability reached 933.1%, 1375.0%, and 1144.4%, respectively. In the model of AD induced by amyloid-beta 1-42 (Aβ1-42), it was confirmed that LK4-TGS-PDA NPs can significantly improve cognitive dysfunction, with escape latency reduced by 30.3%, platform crossings increased by 5.4-fold, and target quadrant time extended by 2.4-fold, as well as reduce the effects of inflammation in the brain, with IL-1β, IL-6, and TNF-α decreased by 44.05%, 53.49%, and 84.40%, respectively. The present investigation outcomes reveal that the engineered LK4-TGS-PDA NPs demonstrates effectiveness and efficiency as a drug delivery approach for the nose-brain pathway, offering valuable insights and prospects for enhancing AD treatment.},
}

@article {pmid42106468,
year = {2026},
author = {Santos, ACC and Corrêa, JL and Duarte, RMF and Malta, SM and Rodrigues, TS and de Oliveira Santos, D and de Faria, PR and do Prado Mascarenhas, FNA and Zanon, RG and Cassemiro, NS and Carollo, CA and Espindola, FS and Martins, MM and Mendes-Silva, AP and Bonetti, AM and Dos Santos, AR and Ueira-Vieira, C},
title = {Bacterial polar metabolites modulate β-amyloid toxicity and cholinergic dysfunction in models of Alzheimer's disease.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-52291-3},
pmid = {42106468},
issn = {2045-2322},
support = {APQ-00269-22//Fundação de Amparo à Pesquisa do Estado de Minas Gerais/ ; 403193/2022-2//Conselho Nacional de Desenvolvimento Científico e Tecnológico/ ; APQ-03613-17; APQ-02766-17//Fundação de Amparo à Pesquisa do Estado de Minas Gerais , Brasil/ ; },
abstract = {Alzheimer's disease is characterized by progressive neurodegeneration driven by β-amyloid (Aβ) toxicity, oxidative stress, and cholinergic dysfunction. In this study, we investigated whether polar metabolites derived from a cultivable bacterial isolate could modulate Aβ-associated neurodegenerative phenotypes in complementary experimental models. A bioactivity-guided approach identified an aqueous fraction with high antioxidant capacity in DPPH, FRAP, and ORAC assays. In a transgenic Drosophila melanogaster model expressing human Aβ, treatment with this fraction significantly reduced amyloid accumulation and attenuated neurodegenerative histopathological alterations. In human SH-SY5Y neuronal cultures, the metabolites improved cell viability under therapeutic, but not preventive, conditions following exposure to aggregated Aβ. The aqueous fraction also exhibited significant inhibitory activity against acetylcholinesterase and butyrylcholinesterase. Whole-genome sequencing assigned the bioactive isolate to the genus Providencia, with comparative genomic analyses suggesting its placement within a distinct taxonomic lineage. Metabolomic profiling by LC-ESI-MS/MS revealed a diverse set of polar metabolites, including metabolites putatively annotated based on spectral matching, previously associated with neuroprotective and cholinesterase-modulating activities. Collectively, these findings demonstrate that bacterial polar metabolites can modulate key pathological features of Alzheimer's disease, supporting their relevance for mechanistic studies of Aβ toxicity and cholinergic dysfunction.},
}

@article {pmid42107415,
year = {2026},
author = {Stepanchuk, AA and Joseph, JT and Lashley, T and Stys, PK},
title = {Disentangling amyloid polymorphs in normal aging and Alzheimer's disease using dual-probe spectral imaging.},
journal = {Neurobiology of aging},
volume = {165},
number = {},
pages = {51-59},
doi = {10.1016/j.neurobiolaging.2026.04.009},
pmid = {42107415},
issn = {1558-1497},
abstract = {Variability in Alzheimer's disease (AD) clinical presentation complicates mechanistic studies and therapeutic outcome prediction. Brain protein aggregate load does not directly correlate with clinical symptoms; however, different subtypes of AD have been reported to exhibit structural variation (polymorphism) of aggregates. Little is known about the structural diversity of the deposits in cognitively normal aged brains. This study investigates the structural heterogeneity of amyloid aggregates in the hippocampus and their association with age- and disease-related pathology. Post-mortem hippocampal tissue from cognitively normal aged controls and AD patients was co-stained with the amyloid-sensitive dyes BSB and MCAAD-3 and imaged across various subregions using spectral fluorescence microscopy. Machine learning analysis of spectral data differentiated amyloid polymorphs between cognitively normal and Alzheimer's cases. Our analysis revealed distinct spectral features across the amyloid plaques, neurofibrillary tangles and the background tissue parenchyma associated with AD compared to those observed in cognitively normal aging, irrespective of overall aggregate load. This study underscores the importance of amyloid polymorphism in determining the clinical impact of protein pathology in AD. Our findings highlight that focusing on amyloid structure rather than total load can aid in advancing personalized approaches in the diagnosis and treatment of neurodegenerative diseases.},
}

@article {pmid42107621,
year = {2026},
author = {Khattab, NA and El Kadeem, A and Goda, AE and El-Mahdy, NA and El-Shitany, N},
title = {Aluminum chloride in Alzheimer's disease: A dual focus on molecular mechanisms and rat experimental models.},
journal = {Experimental neurology},
volume = {403},
number = {},
pages = {115814},
doi = {10.1016/j.expneurol.2026.115814},
pmid = {42107621},
issn = {1090-2430},
abstract = {Alzheimer's disease (AD) is a leading cause of dementia among middle-aged and elderly individuals globally. Animal models of AD are widely used to investigate disease mechanisms and evaluate potential treatments for disease modification. Among non-genetically modified models, aluminum (Al[3+]) induced neurotoxicity has been widely employed to mimic key features of AD, including neuroinflammation and cognitive decline. This review comprehensively elucidates current evidence on the molecular and cellular mechanisms underlying Al[3+]-induced AD-like pathology, including amyloid-β accumulation, tau protein hyperphosphorylation, oxidative stress, mitochondrial dysfunction, neuroinflammation, cholinergic system impairment, synaptic plasticity deficits, apoptosis, metal ion dyshomeostasis, and epigenetic alterations. This review critically discusses methodological variables that significantly influence experimental outcomes in Al[3+]-based models, including dosage, route of administration, exposure duration, and animal age and gender. Moreover, this review emphasizes the translational significance, advantages, and limitations of the Al[3+]-induced model by merging mechanistic insights with experimental design considerations, offering guidelines for its optimal application in AD research and treatment development.},
}

@article {pmid42107748,
year = {2026},
author = {Suriyaamporn, P and Wongprayoon, P and Pannakkong, W and Pamornpathomkul, B and Ngawhirunpat, T and Rojanarata, T and Opanasopit, P},
title = {Development of AI-assisted 3D-printed degradable hydrogel microneedles for transdermal delivery of progesterone-loaded solid lipid nanoparticles: a novel approach to slowing Alzheimer's disease progression.},
journal = {International journal of pharmaceutics},
volume = {},
number = {},
pages = {126967},
doi = {10.1016/j.ijpharm.2026.126967},
pmid = {42107748},
issn = {1873-3476},
abstract = {Progesterone (PG) is used to slow the progression of neurodegenerative diseases, particularly Alzheimer's disease (AD) in postmenopausal women. However, PG exhibits high lipophilicity, resulting in strong binding to skin tissues and plasma proteins, which may limit its systemic transport via transdermal routes. Solid lipid nanoparticles (SLNs) have been highlighted for their potential to enhance drug solubility and facilitate brain-targeted drug delivery for AD treatment. Microneedles (MNs) offer an advanced microtechnology for transdermal drug delivery, significantly improving drug permeation into the skin. However, traditional MNs fabrication methods face challenges related to shape control, dosage precision, high costs, and time consumption. Recent advancements in 3D printing technology offer a promising solution to these limitations. This study aimed to design and evaluate 3D-printed MNs-loaded with PG-SLNs for AD treatment. Biodegradable resin was utilized to fabricate MNs, aided by a Convolutional Neural Networks (CNNs) prediction model for improved accuracy. Mechanical strength, penetration efficiency, degradation, in vitro and in vivo drug delivery efficiency, cellular toxicity, and stability were evaluated. The optimized MNs, with a height of 756.98 ± 14.78 µm, effectively penetrated the skin barrier. SLNs exhibited a particle size of 308.91 ± 1.66 nm, PDI of 0.19 ± 0.08, and ZP of -30.03 ± 1.19 mV. The MNs retained sufficient mechanical strength post-drug loading, enabled efficient transdermal PG delivery, exhibited no cytotoxicity to neuronal cells, and remained physicochemically stable for up to 3 months. This study highlights the potential of 3D-printed MN patches as a novel transdermal drug delivery system, demonstrating practical feasibility for medical applications.},
}

@article {pmid42107892,
year = {2026},
author = {Chen, G and Zhao, C and Wang, C and Chen, G and Shi, J and Chen, H},
title = {Microglia crosstalk with T cells in neurodegenerative diseases: pathogenesis and treatment targets.},
journal = {International immunopharmacology},
volume = {182},
number = {},
pages = {116781},
doi = {10.1016/j.intimp.2026.116781},
pmid = {42107892},
issn = {1878-1705},
abstract = {Immune cells play a central role in driving inflammation and neurodegeneration across various neurological disorders. Central nervous system (CNS)-resident microglia and infiltrating T cells represent the innate and adaptive immune systems, respectively, and have been reported to contribute to the pathogenesis of neurodegenerative diseases individually. Growing evidence suggests that the encounter between activated microglia and infiltrating T cells amplifies their neurotoxic potential. In this review, we discussed alterations in microglial phenotype and function, and the contributions of different T cell subsets in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), Multiple sclerosis (MS), Amyotrophic lateral sclerosis (ALS) and glaucoma. We emphasized the crosstalk between microglia and T cells via antigen presentation, chemotactic signals, and pro-inflammatory mediators. We also explored emerging therapeutic strategies aimed at modulating T cell and microglial responses, as well as their interactions, for the treatment of neurodegenerative diseases.},
}

@article {pmid42108759,
year = {2026},
author = {Meng, Q and Li, J and Xu, G and Zhang, W and Cao, R and Cai, K},
title = {Ginsenoside Rh2 Alleviates Alzheimer Disease Models via Effects on Ferroptosis-Related Neuroinflammation.},
journal = {Journal of biochemical and molecular toxicology},
volume = {40},
number = {5},
pages = {e70860},
doi = {10.1002/jbt.70860},
pmid = {42108759},
issn = {1099-0461},
support = {YKK23216//Nanjing Health Science and Technology Development Special Fund/ ; ST222102//Major Sports Research Projects of Jiangsu Provincial Sports Bureau/ ; LKZ2025004//Jiangsu Elderly Health Scientific Research Project/ ; },
mesh = {Animals ; *Ginsenosides/pharmacology/therapeutic use ; *Alzheimer Disease/drug therapy/metabolism/pathology ; Mice ; Mice, Transgenic ; Disease Models, Animal ; *Ferroptosis/drug effects ; *Neuroinflammatory Diseases/drug therapy/metabolism/pathology ; Amyloid beta-Peptides/metabolism ; Cell Line, Tumor ; Male ; Oxidative Stress/drug effects ; Peptide Fragments ; },
abstract = {Ginsenosides are the primary active constituents derived from the dried roots of ginseng, a staple in traditional Chinese medicine. This study aimed to evaluate the therapeutic efficacy of the Ginsenoside Rh2 (Rh2) monomer in both in vitro and in vivo models of Alzheimer disease (AD). An in vivo AD cell model was established by stimulating N2a mouse neuroblastoma cells with β-amyloid (Aβ) 1-42, while APP/PS1 transgenic mice served as the in vivo model. In vitro, Aβ1-42-stimulated N2a cells were co-incubated with 40 or 80 μM Rh2 for 24 h. In vivo, APP/PS1 mice received daily intraperitoneal injections of Rh2 (20 mg/kg) for 5 weeks. Our results demonstrated that Rh2 treatment significantly enhanced the viability of N2a cells and ameliorated mitochondrial membrane potential dysregulation. Furthermore, Rh2 attenuated oxidative stress by reducing reactive oxygen species production and decreasing malondialdehyde levels. It also suppressed the hypersecretion of pro-inflammatory mediators, including nitric oxide, interleukin-1β (IL-1β), and IL-6, in Aβ-treated cells. Mechanistically, Rh2 exerted potent anti-ferroptotic and anti-inflammatory effects via the activation of the Nrf2/GPX4 signaling pathway, which ultimately translated to improved spatial learning and memory in APP/PS1 mice. These findings elucidate a novel mechanistic paradigm for Rh2, highlighting its potential as a therapeutic candidate for AD drug development.},
}

Animals
*Ginsenosides/pharmacology/therapeutic use
*Alzheimer Disease/drug therapy/metabolism/pathology
Mice
Mice, Transgenic
Disease Models, Animal
*Ferroptosis/drug effects
*Neuroinflammatory Diseases/drug therapy/metabolism/pathology
Amyloid beta-Peptides/metabolism
Cell Line, Tumor
Male
Oxidative Stress/drug effects
Peptide Fragments

@article {pmid42109911,
year = {2026},
author = {Choi, S and Park, S and Jung, YH and Oh, MS and Yu, KH and Lee, BC and Lee, M},
title = {Comparative risk of dementia between direct oral anticoagulants and warfarin after atrial fibrillation related ischemic stroke.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1718536},
pmid = {42109911},
issn = {1663-4365},
abstract = {INTRODUCTION: Direct oral anticoagulants (DOAC) have been associated with a reduced risk of dementia compared to warfarin in patients with atrial fibrillation (AF) without prior stroke. However, the impact of DOAC on dementia risk in AF-related ischemic stroke survivors is unclear.

METHODS: We conducted a retrospective, nationwide cohort study using the Korean National Health Insurance Service database. We identified patients with newly diagnosed ischemic stroke and concurrent AF who began DOAC or warfarin therapy within one month after stroke. Incidence of all-cause dementia, Alzheimer's dementia (AD), and vascular dementia (VaD) was compared between groups using multivariable Cox models with inverse probability of treatment weighting.

RESULTS: A total of 3,112 patients (mean age 70.6 ± 9.5 years; 66.6% male) were analyzed, including 2,919 DOAC users and 193 warfarin users. Over a mean follow-up of 3.63 years, 673 all-cause dementia cases (538 AD, 168 VaD) occurred. After IPTW, DOAC use was associated with higher risks of all-cause dementia (HR 1.16, 95% CI 1.04-1.30) and AD (HR 1.85, 95% CI 1.62-2.13) but a lower risk of VaD (HR 0.54, 95% CI 0.45-0.66) compared to warfarin.

DISCUSSION: In this retrospective nationwide cohort of AF-related ischemic stroke survivors, DOAC use was associated with a higher incidence of all-cause dementia and Alzheimer's dementia, but a lower incidence of vascular dementia, compared with warfarin. These observational findings suggest that anticoagulant type may be differentially associated with subsequent dementia subtypes in this high-risk population and should be interpreted with caution.},
}

@article {pmid42109914,
year = {2026},
author = {Fu, X and Huang, J and Liu, Y and Li, H and Zhang, Y},
title = {Unraveling the anti-neuroinflammatory mechanisms of Cervus cucumis polypeptide injection in Alzheimer's disease: insights from network pharmacology, molecular docking, molecular dynamics simulation, and experimental validation.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1797302},
pmid = {42109914},
issn = {1663-4365},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder with increasing global prevalence, in which neuroinflammation serves as a critical pathological driver exacerbating cognitive decline. While current therapies offer limited symptomatic relief, multi-target strategies are urgently needed. Cervus cucumis polypeptide injection (CCPI), a traditional Chinese medicine (TCM) formulation, has demonstrated anti-inflammatory properties; however, its mechanisms of action against AD remain unclear. This study aimed to elucidate the anti-AD potential mechanisms of CCPI using an integrated approach combining network pharmacology, molecular docking, molecular dynamics (MD) simulation, and experimental validation.

METHODS: Active components and corresponding targets of CCPI were retrieved from the TCMSP database, while AD-related targets were collected from Genecards, OMIM, and DrugBank. Potential therapeutic targets were identified by intersecting drug and disease targets, followed by protein-protein interaction (PPI) network construction, Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. Molecular docking and MD simulations were performed to evaluate interactions between potential active components and key targets. In vitro experiments were conducted on Aβ25-35-induced BV2 microglial cells to assess cell viability (CCK-8 assay), inflammatory cytokine levels (ELISA), and protein expression (Western blot) related to the neuroinflammation pathway and microglial polarization.

RESULTS: A total of 28 active components and 50 common targets of CCPI for AD treatment were identified. Linoleic acid (LA) was determined to be a potential active component, with IL-6 as the key target based on PPI network topology. Molecular docking and MD simulation confirmed a stable binding affinity between LA and IL-6. KEGG analysis revealed significant enrichment in the HIF-1 signaling pathway, particularly the IL-6/STAT3/VEGF signaling pathway. In vitro, CCPI treatment significantly enhanced cell viability and attenuated the pro-inflammatory response, as evidenced by reduced levels of IL-6, IL-1β, and TNF-α, decreased the expression of the pro-inflammatory marker iNOS. Concurrently, it elevated the expression of the anti-inflammatory/repair-associated marker CD206. Western blot analysis further verified that CCPI suppressed IL-6/STAT3 activation while upregulating VEGF expression. Additionally, LA alone significantly reduced IL-6 levels and STAT3 phosphorylation, decreased the expression of iNOS, and increased the expression of CD206, with therapeutic efficacy comparable to CCPI.

CONCLUSION: CCPI exerts neuroprotective effects in AD models by regulating the IL-6/STAT3/VEGF pathway, downregulating the expression of the inflammation-related iNOS protein, upregulating the expression of the CD206 protein associated with anti-inflammatory and reparative functions, remodeling the functional state of microglia, inhibiting their pro-inflammatory responses, and enhancing their reparative functions. Its potential active component, LA, likely mediates this effect by stably binding to and inhibiting IL-6, thus suppressing the downstream STAT3 phosphorylation that drives inflammatory activation.},
}

@article {pmid42100782,
year = {2026},
author = {Zhang, R and Sun, H and Di, Y and Cao, H and Zhang, C and Yao, H and Yan, H and Ding, D and He, Q and Wu, T},
title = {Sleep quality metrics combined with virtual reality motion parameters enhance early detection of mild cognitive impairment.},
journal = {Frontiers in psychiatry},
volume = {17},
number = {},
pages = {1727576},
pmid = {42100782},
issn = {1664-0640},
abstract = {OBJECTIVE: Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive and motor deficits. With its global prevalence increasing rapidly and no effective treatment available, early identification of high-risk individuals is critical. This study investigated the relationship between motor parameters extracted from virtual reality (VR) tasks, combined with sleep-related measures, and cognitive impairment in patients with mild cognitive impairment (MCI). Our goal was to determine whether integrating VR-derived digital markers with sleep quality metrics could provide an objective and clinically applicable tool for early detection.

METHODS: 66 participants were recruited, including 28 healthy controls (HC) and 38 patients with MCI. Cognitive status was assessed using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). All participants performed two scenario-based VR tasks, during which task completion time, accuracy, and overall performance scores were recorded. Group differences were evaluated using independent-samples t-tests, and these behavioral features and sleep quality metrics were further incorporated into ROC analyze to assess predictive performance for distinguishing MCI from HC.

RESULTS: Compared with HC, patients with MCI reported significantly poorer sleep quality based on the Pittsburgh Sleep Quality Index (PSQI) and subdomains such as sleep latency and habitual sleep efficiency. In the VR tasks, MCI patients required more time and achieved lower accuracy than HC, consistent with MoCA and MMSE scores. Correlation analysis confirmed strong associations between VR performance metrics and cognitive test scores. Importantly, integrating VR-derived digital markers with sleep parameters yielded superior predictive accuracy for MCI (AUC = 0.863; sensitivity = 86.84%; specificity = 71.43%; p < 0.001) compared with single-modality models.

CONCLUSION: VR-based cognitive and sensorimotor tasks, when combined with sleep quality assessments, offer a robust and noninvasive approach for the early identification of prodromal AD. This multimodal strategy holds promise for enhancing clinical decision-making and enabling timely interventions.},
}

@article {pmid42100836,
year = {2026},
author = {Kaczmarek-Kryszak, KA and Dobrzyńska, M and Banaszak, M and Drzymała-Czyż, S},
title = {A comprehensive systematic review of human trials investigating herbal treatments for Alzheimer's disease and dementia.},
journal = {Acta neuropsychiatrica},
volume = {},
number = {},
pages = {1-55},
doi = {10.1017/neu.2026.10085},
pmid = {42100836},
issn = {1601-5215},
abstract = {OBJECTIVE: Dementia is a group of symptoms, characterized by a loss of cognition that interferes with everyday tasks, difficulty focusing, planning, problem solving, and behavioral changes, such as apathy, anxiety, or depression. The leading cause of dementia is Alzheimer's disease, but vascular dementia or mild cognitive impairment are also frequently occurring. There are six drugs legislated in Europe for use in the treatment of dementia. There are unmet clinical needs to find more effective, better tolerated or complementary therapeutic options. The aim of this study is to comprehensively analyze the results of clinical trials and other human studies regarding the efficacy and safety of herbal interventions used in patients with dementia.

METHODS: We enrolled a total of 48 studies for this systematic review, of which 27 were included into the statistical analysis of effect size (Cohen's d).

RESULTS: We found significant improvements mainly after administration of Ginkgo biloba, Crocus sativus, Salvia officinalis, and Melissa officinalis.It should be emphasized that some herbs and herbal formulations demonstrated efficacy comparable to that of donepezil, a widely used and approved medication, suggesting potential for phytopharmaceutical therapies as complementary approaches. In some studies, the observed effects were similar to those reported for conventional treatments, indicating promising directions for further research in Alzheimer's disease and dementia.

CONCLUSION: In light of the evidence, phytopharmaceuticals have a promising role as a co-therapeutic option or alternative for patients with dementia who do not tolerate or have contraindications to standard medications. However, further research is necessary to translate these initial promising results into clinical practice.

SUMMATIONS: Phytopharmaceuticals have a promising role as a complementary or alternative option for dementia patients who cannot tolerate or respond to standard medications. Certain phytopharmaceuticals demonstrated comparable short-term symptomatic effects to standard treatments in small trials; however, evidence is insufficient to support equivalence or superiority.

CONSIDERATIONS: Many of the studies reviewed are limited by very small sample sizes, which is associated with a high risk of bias when interpreting large effect sizes (Cohen's d). The short duration of interventions (often only 3 to 6 months) is insufficient to assess whether phytotherapeutics can constitute disease-modifying treatments (DMTs).},
}

@article {pmid42101516,
year = {2026},
author = {Zhou, B and Wu, X and Wang, J and Li, L and Xu, H and Shao, W},
title = {Compatibility of Acorus tatarinowii Schott and Polygala tenuifolia Willd. alleviate Alzheimer's disease through regulating Nos2-mediated calcium signaling pathway.},
journal = {Neurochemical research},
volume = {51},
number = {3},
pages = {},
pmid = {42101516},
issn = {1573-6903},
support = {ZY2023M027//the General Project of the Administration of Traditional Chinese Medicine of Hubei Province/ ; },
mesh = {PC12 Cells ; Animals ; *Alzheimer Disease/drug therapy/metabolism ; Rats ; Amyloid beta-Peptides/metabolism ; *Polygala/chemistry ; *Calcium Signaling/drug effects/physiology ; *Nitric Oxide Synthase Type II/metabolism ; *Acorus/chemistry ; *Plant Extracts/pharmacology/therapeutic use ; Cell Survival/drug effects ; Peptide Fragments/metabolism ; },
abstract = {Herb pair of Acorus tatarinowii Schott (ATS) and Polygala tenuifolia Willd. (PTW) is a classic drug pair in the treatment of Alzheimer's disease (AD), However, the mechanism by which the drug pair acts on AD is currently unknown. To address this, we constructed a PC12 cellular AD model using amyloid-beta peptide (Aβ) (25-35), follow by treating with different concentrations of ATS and PTW alone or their combination (1:1). The cell viability and Aβ-40, Aβ-42 and AQP4 expression were detected. In addition, RNA-sequencing combined with network pharmacology was performed to investigate the action mechanism of ATS and PTW, and the results were validated using in vitro experiments. The results showed that at drug-acting concentrations less than 100 mg/L, both single-agent and combined treatments of ATS and PTW increased the protective effects on PC12 cell, and the herb pair was superior to single-agent. In addition, both single-agent and combined treatments of ATS and PTW (at concentration of 100 mg/L) decreased Aβ-40, Aβ-42 and AQP4 expression compared with AD model. Further RNA-sequencing combined with network pharmacology analysis suggested that the underline action mechanism might be associated with Nos2-mediated calcium signaling pathway regulated. In vitro validation experiments showed that Nos2 overexpression increase the levels of Aβ-40, Aβ-42, AQP4, p-Tau, CaM, and p-CaMKII, which were reversed by the combination treatment of ATS and PTW. In conclusion, this work indicates that ATS and PTW combination might alleviate an Aβ-induced cellular model through regulating Nos2 - mediated calcium signaling pathway.},
}

PC12 Cells
Animals
*Alzheimer Disease/drug therapy/metabolism
Rats
Amyloid beta-Peptides/metabolism
*Polygala/chemistry
*Calcium Signaling/drug effects/physiology
*Nitric Oxide Synthase Type II/metabolism
*Acorus/chemistry
*Plant Extracts/pharmacology/therapeutic use
Cell Survival/drug effects
Peptide Fragments/metabolism

@article {pmid42103387,
year = {2026},
author = {Laugesen, K and Skjærbæk, C and Okkels, N and Møller, HJ and Borghammer, P and Gottrup, H and Parkner, T},
title = {ODIN Biobank: a Danish cohort for dementia research- cohort profile.},
journal = {BMJ open},
volume = {16},
number = {5},
pages = {e114084},
doi = {10.1136/bmjopen-2025-114084},
pmid = {42103387},
issn = {2044-6055},
mesh = {Humans ; Female ; Denmark ; Male ; Aged ; *Biological Specimen Banks ; *Dementia/cerebrospinal fluid/blood/diagnosis ; Biomarkers/cerebrospinal fluid/blood ; Aged, 80 and over ; Cohort Studies ; Middle Aged ; Alzheimer Disease/cerebrospinal fluid/blood ; Cognitive Dysfunction/cerebrospinal fluid/blood ; },
abstract = {PURPOSE: Biomarkers related to the diagnosis, prognosis and treatment of dementia will play a key role in future clinical practice. The overarching aim of the ODIN (blood and cerebrospinal fluid) Biobank is to study biomarkers for dementia and contribute to the transition from cerebrospinal fluid to blood-based biomarkers.

PARTICIPANTS: ODIN recruited 451 patients (median age 74 years, 53% females) referred to the Department of Neurology at Aarhus University Hospital, Denmark, for diagnostic assessment of dementia. Enrolment started in March 2020 and ended in July 2025. Patients referred for a lumbar puncture were eligible for inclusion. Cerebrospinal fluid and blood samples (plasma, serum and buffy coat) were stored at -80°C. Information about sociodemographic, educational level, dementia subtype, cognitive test scores, neuroimaging results, hypertension, diabetes, height, weight, alcohol consumption and smoking was collected.

FINDINGS TO DATE: The most frequent diagnoses were Alzheimer's disease (n=268, 59%), frontotemporal dementia (n=26, 5.8%) and mixed Alzheimer's and vascular disease (n=23, 5.1%). N=82 (18%) were cognitively unimpaired or had mild cognitive impairment but not dementia. The median Mini-Mental State Examination score was 23 (IQR: 20-26) and the median Addenbrooke's Cognitive Examination score was 68 (IQR: 58-77).

FUTURE PLANS: ODIN will contribute to the development, validation and implementation of new biomarkers related to diagnosis, prognosis and treatment of dementia. Furthermore, the cohort will assist the transition from cerebrospinal fluid to blood-based biomarkers.},
}

Humans
Female
Denmark
Male
Aged
*Biological Specimen Banks
*Dementia/cerebrospinal fluid/blood/diagnosis
Biomarkers/cerebrospinal fluid/blood
Aged, 80 and over
Cohort Studies
Middle Aged
Alzheimer Disease/cerebrospinal fluid/blood
Cognitive Dysfunction/cerebrospinal fluid/blood

@article {pmid42104655,
year = {2026},
author = {Sharmin, T and Doecke, JD and Chatterjee, P and Pedrini, S and Sohrabi, HR and Ashton, NJ and Zetterberg, H and Garg, ML and Blennow, K and Martins, RN},
title = {Circulating Sphingomyelins Correlate With Plasma T-Tau in Cognitively Unimpaired Older Adults at Risk of Developing Alzheimer's Disease.},
journal = {Journal of neurochemistry},
volume = {170},
number = {5},
pages = {e70436},
pmid = {42104655},
issn = {1471-4159},
support = {2018-02532//MQ Research Seeding Grant, Macquarie University/ ; 681712//MQ Research Seeding Grant, Macquarie University/ ; 201809-2016862//MQ Research Seeding Grant, Macquarie University/ ; 2017-00915//MQ Research Seeding Grant, Macquarie University/ ; FO2017-0243//MQ Research Seeding Grant, Macquarie University/ ; JPND2019-466-236//MQ Research Seeding Grant, Macquarie University/ ; //Macquarie University HDR Fund, Macquarie University/ ; 101053962//European Union's Horizon Europe research and innovation programme/ ; 2019-02397//Swedish Research Council/ ; },
mesh = {Humans ; Female ; Aged ; *tau Proteins/blood ; Male ; *Alzheimer Disease/blood/diagnostic imaging/psychology ; *Sphingomyelins/blood ; Cross-Sectional Studies ; Positron-Emission Tomography ; Aged, 80 and over ; Biomarkers/blood ; Amyloid beta-Peptides/metabolism ; Cognition/physiology ; Cohort Studies ; },
abstract = {Alterations in plasma sphingomyelin (SM) levels have been reported in Alzheimer's disease (AD), pointing to disturbances in lipid metabolism that may contribute to disease pathogenesis. Neuronal damage in early AD triggers tau release into central and peripheral systems. Despite influence from peripheral contributions, alterations in plasma total-tau (T-tau) remain valuable in indicating AD-related neurodegeneration. Investigating relationships between SM metabolism and tau release during preclinical AD may uncover important biochemical processes and support advancing early non-invasive detection and treatment approaches. This cross-sectional study investigated cognitively unimpaired (CU) older adults from the KARVIAH cohort, grouped by cortical amyloid-β (Aβ) status through positron emission tomography (PET) imaging (CU Aβ- and CU Aβ+) and utilised a Biocrates-targeted metabolomic platform and Single-molecule array (Simoa) technology to quantify plasma levels of SMs and T-tau, respectively. Associations between circulating SMs and T-tau were examined within each group, with T-tau-associated SMs further evaluated for their association with cognitive performance and cortical Aβ burden and their potential to discriminate CU Aβ+ from CU Aβ- individuals. Significant positive correlations were observed between SMs and T-tau levels exclusively in CU Aβ+ individuals, suggesting connections between SM-mediated biochemical pathways and tau release from early neurodegeneration in preclinical AD. Lower SM levels were associated with weaker working memory and executive function, as well as poorer global cognition, indicating their potential predictive value for weaker cognitive performance. Moreover, SMs were also inversely associated with cortical Aβ load in CU Aβ+ individuals, possibly reflecting early SM-mediated neuroprotective responses against AD pathogenesis. Receiver operating characteristic analysis further revealed the significant potential of the SM panel in distinguishing cortical PET-Aβ status and enhancing the predictive performance of plasma T-tau in CU individuals. Therefore, circulating T-tau-associated SMs may serve as promising early biomarkers of lipid-mediated processes in CU older adults with cortical amyloid pathology and tau-related neurodegeneration.},
}

Humans
Female
Aged
*tau Proteins/blood
Male
*Alzheimer Disease/blood/diagnostic imaging/psychology
*Sphingomyelins/blood
Cross-Sectional Studies
Positron-Emission Tomography
Aged, 80 and over
Biomarkers/blood
Amyloid beta-Peptides/metabolism
Cognition/physiology
Cohort Studies

@article {pmid42105317,
year = {2026},
author = {Balwant Patil, K and Sugunan, S and Padiyar, A and Mishra, AK and Jain, S},
title = {Neuroprotective role of phenolic acids: mechanistic insights into cognitive decline and neurodegenerative disorder.},
journal = {Nutritional neuroscience},
volume = {},
number = {},
pages = {1-25},
doi = {10.1080/1028415X.2026.2669234},
pmid = {42105317},
issn = {1476-8305},
abstract = {BACKGROUND: Age-associated cognitive deterioration and neurodegenerative conditions, including Alzheimer's disease (AD) and Parkinson's disease (PD), are predominantly influenced by oxidative stress, neuroinflammation, mitochondrial dysfunction, and abnormal protein aggregation. Dietary phenolic acids, prevalent in plant-based foods, have demonstrated potential neuroprotective and cognitive-enhancing effects in recent studies.

PURPOSE: This review seeks to thoroughly assess the neuroprotective mechanisms of phenolic acids and to consolidate existing evidence from human and preclinical studies concerning their potential efficacy in alleviating cognitive impairment and neurodegeneration.

STUDY DESIGN: Narrative and evidence-based literature review.

METHODS: Recent experimental, clinical, and epidemiological studies examining significant phenolic acids - such as caffeic, chlorogenic, ferulic, gallic, rosmarinic, sinapic, ellagic, protocatechuic, p-coumaric, and tannic acids - in relation to AD, PD, and cognitive functions were retrieved from electronic databases. We put together the most important information about molecular mechanisms and treatment.

RESULTS: Preclinical studies show that phenolic acids have antioxidant, anti-inflammatory, anti-apoptotic, and anti-aggregation effects by changing important signaling pathways like Nrf2/HO-1, NF-κB, and PI3 K/Akt. These actions protect dopaminergic neurons, lower the toxicity of amyloid-beta and α-synuclein, and make behavior better in disease models. Human studies suggest that increased dietary consumption of phenolic acids, especially hydroxycinnamic acids such as caffeic and chlorogenic acid, is associated with enhanced cognitive performance and a diminished risk of cognitive decline, although results are not uniform.

CONCLUSION: Phenolic acids are secure, readily accessible neuroprotective compounds that can alter various pathological pathways associated with cognitive decline and the progression of neurodegenerative diseases.},
}

@article {pmid42105452,
year = {2026},
author = {Uehara, MA and Bretecher, CA and Teschuk, JM and Verot, A and Saha, C and Fitzgerald, PB and Koski, L and Millikin, C and Moussavi, Z},
title = {Examining adverse effects in a large clinical trial of rTMS application as a treatment for Alzheimer's disease.},
journal = {Psychiatry research},
volume = {362},
number = {},
pages = {117212},
doi = {10.1016/j.psychres.2026.117212},
pmid = {42105452},
issn = {1872-7123},
abstract = {BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) has several advantages compared to other interventions for neurological and psychological disorders. However, various adverse effects have been reported in rTMS research, and little is known about who is most susceptible to rTMS adverse effects, or how they can be minimized.

AIMS: We aimed to identify risk factors for adverse effects reported in a recent clinical trial examining rTMS as a treatment for Alzheimer's disease (AD). We hypothesized that higher stimulation intensity would be associated with experiencing unspecified pain/discomfort, dental pain, headache, jaw pain, and muscle contractions, but not be associated with other adverse effects.

METHODS: Using detailed notes from treatment sessions, 10 adverse effects were identified. Spearman correlations were conducted to assess relationships between the highest applied stimulation intensity and normalized frequency of each adverse effect amongst those who experienced that adverse effect. Demographic information, cognitive scores, and withdrawal status were compared between the binarized groups of participants who experienced adverse effects versus those who did not. Spearman correlations were also conducted on the binarized adverse effects and the highest applied stimulation intensity. Logistic regressions were conducted to identify potential risk factors.

RESULTS: In both the sham and active treatment groups, unspecified pain/discomfort was the most common adverse effect, followed by muscle contractions and dizziness. In both the active and sham treatment groups, stimulation intensity was positively associated with muscle contractions, but was not significantly related to any other adverse effect. In evaluating groups with/without adverse effects, we found there was a significantly higher proportion of males reporting adverse effects in both the active treatment group and the sham treatment group compared to females.

CONCLUSION: The findings of this study are a step toward understanding how researchers can minimize such adverse effects, and thereby, create a less aversive experience for rTMS participants.},
}

@article {pmid42105933,
year = {2026},
author = {Pourzal, R and Agarwal, P and Leurgans, SE and McCarthy, SM and Hall, DJ and McDevitt, CA and Ganio, K and Ayton, S and Bush, AI and Grodstein, F and James, B and Agrawal, S and Hallab, NJ and Bennett, DA and Schneider, JA and Jacobs, JJ},
title = {Cobalt and titanium levels in the brain are associated with Alzheimer's disease pathology but not cognition: A study of older adults with and without total joint replacement.},
journal = {Acta biomaterialia},
volume = {},
number = {},
pages = {},
doi = {10.1016/j.actbio.2026.05.006},
pmid = {42105933},
issn = {1878-7568},
abstract = {Alzheimer's disease (AD) and total joint arthroplasty are prevalent and often concomitant in older adults, but an etiologic link is debated. Since wear particles are an inevitable side product of total joint arthroplasty (TJA), we hypothesized that older adults with TJA agglomerate higher-than-normal concentrations of implant alloy elements caused by the dissemination of debris from the implants, resulting in a pathological reaction. A cross-sectional analysis was conducted among 701 autopsied participants of an ongoing longitudinal cohort (Memory and Aging Project (MAP)) of whom postmortem neuropathologic data was available and implant-related metals (cobalt, titanium) were quantified in four brain regions by inductively coupled mass-spectrometry. MAP participants are enrolled without known dementia at baseline and followed annually for cognitive assessments using 19-test battery. In the analytical sample, 229 had TJA (total hip arthroplasty, total knee arthroplasty, and total shoulder arthroplasty) and n=472 had no total joint. Due to a higher likelihood of cobalt release in total hip arthroplasty, the TJA group was subdivided into a hip (n=146) and a knee/shoulder (n=83) group. We used regression and linear mixed-effects models, adjusted for demographics and apolipoprotein E ε4 status, to examine associations between metals, AD pathology and cognitive decline. Cobalt content of brain tissue was 8.9% higher in the total hip arthroplasty group than in the no-TJA group (p=0.003). Cobalt-containing particles were identified within brain tissue using scanning electron microscopy. In the inferior temporal cortex, cobalt was positively associated (p=0.0004) and titanium was negatively associated (p=0.038) with amyloid-beta load, but had no association with cognition. These results warrant monitoring the potential impact of metal implant debris on brain health. STATEMENT OF SIGNIFICANCE: This study is of great clinical significance because Alzheimer's disease (AD) and total joint arthroplasty (TJA)-the end-stage treatment of osteoarthritis-affect large and overlapping groups in our aging population. There is limited knowledge about the relationship between the prominent TJA implant metals cobalt and titanium and the pathogenesis of AD. This study shows that Co28Cr6Mo and Ti6Al4V implant alloy particles-most likely from a subset of total hip replacements with accelerated wear or tribocorrosion-can disseminate to the brain and be associated with increased cobalt and titanium concentrations. Cobalt was associated with greater AD pathology in the inferior-temporal cortex, even after correction for other known AD risk factors. However, there was no correlation with cognitive decline. Titanium was negatively associated with AD pathology, but titanium oxide appeared to be abundant in the brain from sources other than joint replacements.},
}

@article {pmid41906135,
year = {2026},
author = {Yang, R and He, Y and Pan, Y and Geng, A and Huang, F and Guo, K and Zhang, H},
title = {Multiparity exacerbates Aβ accumulation and promotes cellular senescence in a mouse model of amyloidosis.},
journal = {Immunity & ageing : I & A},
volume = {23},
number = {1},
pages = {},
pmid = {41906135},
issn = {1742-4933},
support = {82271472//the National Natural Science Foundation of China grants/ ; },
abstract = {BACKGROUND: Women have nearly twice the lifetime risk of Alzheimer’s disease (AD) as men. Hormonal and reproductive factors have been implicated; however, the role of parity, a female-specific experience, remains unknown. While epidemiological data suggest that high parity may increase the risk of dementia, the underlying biological mechanisms are unclear.

METHODS: We investigated the impact of multiparity on AD pathology using 2-month-old female 5xFAD mice. Mice were assigned to a nulliparous (0x) or multiparous (4x) (four consecutive gestation cycles) group. Brain tissues were analyzed at 6.4 months of age for Aβ pathology, neuroinflammation, synaptic markers, and senescence. Proteomic profiling and in vitro hormone treatment identified the key mediators. The role of voluntary running was assessed in a separate cohort of nulliparous mice.

RESULTS: Multiparous 5xFAD mice showed increased Aβ plaque burden, elevated BACE1 expression, synaptic loss, and activated senescence pathways compared to nulliparous controls. Proteomic analysis revealed sustained upregulation of the transcription factor FOSB. FOSB was found to drive BACE1 expression and Aβ production. In vitro co-treatment with estradiol and progesterone increased FOSB and BACE1 levels, supporting the presence of a hormone-responsive regulatory link. In nulliparous female 5xFAD mice, voluntary running from 2 to 6 months of age reduced Aβ deposition, fewer FOSB[+] neurons, and microglial activation compared with those in the sedentary controls.

CONCLUSIONS: Our findings identified the FOSB/BACE1 signaling axis as a link between reproductive history and AD pathology. Multiparity accelerates amyloid pathology and brain aging in female 5xFAD mice, mechanistically linked to hormone-driven FOSB upregulation. Physical activity downregulates this pathway in nulliparous animals. Whether exercise can mitigate parity-associated pathology remains to be investigated in multiparous animal models.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12979-026-00565-9.},
}

@article {pmid41913175,
year = {2026},
author = {Ito, K and Tsuda, S and Wake, T and Hatakeyama, A and Ogisawa, F and Ono, M and Nakayama, R and Wakui, T and Nagano, N and Iwata, A},
title = {Reframing dementia care in the era of disease-modifying therapies: informational, psychosocial, and systemic insights from Japan.},
journal = {BMC health services research},
volume = {26},
number = {1},
pages = {},
pmid = {41913175},
issn = {1472-6963},
support = {25K14240//Grants-in-Aid for Scientific Research/ ; 25GB0301//Health and Labor Sciences Research Grant/ ; },
abstract = {BACKGROUND: The introduction of disease-modifying therapies (DMTs) for Alzheimer’s disease has prompted major changes in diagnostic pathways, referral processes, and service coordination in dementia care. Japan, as an early adopter of DMTs within a nationally coordinated dementia-care framework, offers an opportunity to examine how health service structures respond to these changes. This study explored health service–related support needs emerging across the DMT pathway, focusing on patient and informal caregiver experiences, with complementary perspectives from service providers.

METHODS: A qualitative study was conducted using semi-structured interviews with 48 participants, including nine patients who underwent DMT eligibility assessment, seven informal caregivers, 11 physicians, four nurses, five clinical psychologists, five social workers, and seven community-based dementia support providers. Data were analyzed using the Framework Method, an applied qualitative approach suitable for health services research. Patients’ and caregivers’ accounts were treated as the primary analytic focus, while provider perspectives were used to contextualize system-level factors influencing care delivery.

RESULTS: Three interrelated themes were identified. First, informational support needs reflected inequitable access to trustworthy information, difficulties in sustaining understanding of complex medical explanations, and a lack of structured opportunities to revisit information over time, particularly during transitions such as ineligibility, treatment discontinuation, or completion. Second, psychosocial support needs were closely shaped by service processes, including stigma-related experiences across clinical and social contexts, family-related tensions around treatment decisions, fluctuating expectations regarding treatment effects, and limited support for adjustment when DMT was no longer an option. Third, systemic and collaborative support needs highlighted fragmented roles between primary care and DMT-designated institutions, unclear referral and handover pathways, insufficient psychosocial care capacity, and weak integration between DMT delivery systems and existing dementia-care services.

CONCLUSIONS: The implementation of DMTs has amplified pre-existing gaps in dementia care systems, revealing previously underrecognized structural vulnerabilities across informational, psychosocial, and systemic domains. Findings indicate that DMTs should be embedded within coordinated care pathways that ensure continuity of information provision, access to psychosocial support, and clear allocation of follow-up responsibility regardless of treatment eligibility. Aligning pharmacological innovation with health service design is essential to support equitable, continuous, and person-centered dementia care.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12913-026-14472-8.},
}

@article {pmid42100730,
year = {2026},
author = {Copeland, EN and Marais, AAT and Mohammad, A and Marcella, BM and Baranowski, RW and Beaudette, SM and MacPherson, REK and Fajardo, VA},
title = {Tideglusib improves novel object recognition memory in the preclinical DBA/2J mdx mouse model of Duchenne muscular dystrophy.},
journal = {Frontiers in neuroscience},
volume = {20},
number = {},
pages = {1812975},
pmid = {42100730},
issn = {1662-4548},
abstract = {INTRODUCTION: Duchenne muscular dystrophy (DMD) is a severe X-linked neuromuscular disorder characterized by progressive muscle wasting. Approximately 1 in 3 DMD patients experience cognitive dysfunction, with research suggesting an Alzheimer's disease (AD)-like pathology. We have previously shown that treatment with the glycogen synthase kinase 3β (GSK3) inhibitor, tideglusib, improves muscle quality, function, and insulin sensitivity in the DBA/2J (D2) mdx mouse model of DMD. In this brief follow-up study, we report the effects of tideglusib treatment on cognitive function.

METHODS: Male D2 WT and mdx mice were purchased from Jackson Laboratories. Mice were separated into the following groups: (1) WT, (2) mdx-vehicle, and (3) mdx-tideglusib (10 mg/kg/day via oral gavage for 4 weeks). A novel object recognition test was performed to assess recognition memory. Hippocampus and serum samples were collected for BACE1 activity assays, amyloid beta (Aβ) ELISAs, and western blotting.

RESULTS: Compared to vehicle-treated mdx mice, tideglusib-treated mdx mice demonstrated improved recognition memory. These changes to recognition memory were accompanied by greater expression of beta-catenin, an indirect downstream marker of GSK3 inhibition. While there were no changes in BACE1 activity, tideglusib-treated mdx mice had higher concentrations of Aβ in the serum and lower protein levels of receptor of advanced glycation end products.

DISCUSSION: The results from this brief follow-up study offer preliminary support for tideglusib as a treatment for both muscle and brain impairments in mdx mice, potentially improving cognitive function through enhanced vascular Aβ clearance.},
}

@article {pmid42097410,
year = {2026},
author = {Zhu, PF and Lyu, Z and Wang, Q and Li, S and Wang, X and Luo, A},
title = {ISRIB as a Prototype eIF2B Activator: Pharmacology, Mechanisms, and Translational Potential in Aging-Related Cognitive Disorders.},
journal = {Pharmacological research},
volume = {},
number = {},
pages = {108228},
doi = {10.1016/j.phrs.2026.108228},
pmid = {42097410},
issn = {1096-1186},
abstract = {Aging-related cognitive disorders have been increasingly linked to maladaptive stress pathways that persistently impair synaptic protein synthesis and plasticity. The integrated stress response (ISR) links various stressors to downstream translational reprogramming through the phosphorylation of eIF2α. Acute ISR activation can be protective, while chronic ISR activation may confine neurons and glial cells to hypo-plastic states, impairing learning and memory function. ISRIB is a prototype small molecule that activates eIF2B and restores translation homeostasis, providing a viable framework for "tuning" ISR output rather than indiscriminately blocking stress signaling. This review summarizes ISR biology in the aging brain, emphasizes cell-type heterogeneity, and evaluates the evidence for ISRIB across various conditions, including normal aging, Alzheimer's disease, vascular cognitive impairment, synucleinopathies, perioperative neurocognitive disorders, and related conditions with shared ISR pathology. We then discuss dosing, safety, optimization, limitations, translational biomarkers, and lessons from emerging clinical-stage eIF2B activators. Finally, we propose precision and combination strategies to tailor ISR modulation to disease stage, pathological context, and therapeutic window, aiming to provide new directions and a theoretical basis for the treatment of aging-related cognitive disorders.},
}

@article {pmid42097478,
year = {2026},
author = {Matošević, A and Maraković, N and Barić, D and Igert, A and Brazzolotto, X and Kovarik, Z and Bosak, A},
title = {Integrative Structural and Kinetic Analysis of the Molecular Basis for Reduced Carbamate Inhibition in Atypical Butyrylcholinesterase.},
journal = {Chemico-biological interactions},
volume = {},
number = {},
pages = {112134},
doi = {10.1016/j.cbi.2026.112134},
pmid = {42097478},
issn = {1872-7786},
abstract = {Butyrylcholinesterase (BChE) plays a key role in cholinergic transmission and the metabolism of various drugs, making its regulation a promising therapeutic strategy for several diseases, including Alzheimer's disease. Selective inhibition of BChE helps regulate brain acetylcholine levels. However, genetic polymorphisms in the BCHE gene, particularly the Asp70Gly mutation in atypical BChE, can impact treatment outcomes. This study compares the inhibitory potency of 13 carbamates against atypical and usual BChE. Using molecular docking, quantum chemical cluster calculations, and crystallization of wild-type BChE with the most potent carbamate, we identified key differences in carbamylation mechanisms. Atypical BChE shows a less favorable enzyme-inhibitor complex orientation, lacking the hydrogen bond stabilization of the reactive carbonyl oxygen. Additionally, Asp70 in usual BChE contributes to stabilizing the non-reactive carbamate group, whereas Gly70 in atypical BChE is too distant to form such interactions.},
}

@article {pmid42097853,
year = {2026},
author = {Rohatgi, S and Omid-Fard, N and Zhu, S and Martinez Imbett, RE and Ford, JN and Dowling, TP and Kirsch, JE and Romero, JM},
title = {Relationship of Inferior Frontal Sulcal Hyperintensities with Amyloid-Related Imaging Abnormalities.},
journal = {AJNR. American journal of neuroradiology},
volume = {},
number = {},
pages = {},
doi = {10.3174/ajnr.A9395},
pmid = {42097853},
issn = {1936-959X},
abstract = {OBJECTIVE: Anti-amyloid immunotherapies used to treat Alzheimer's disease (AD) are often associated with amyloid-related imaging abnormalities (ARIA). We aim to indirectly assess glymphatic function by using inferior frontal sulcal hyperintensity (IFSH) as a biomarker in patients receiving anti-amyloid therapy, both with and without ARIA, as well as in healthy controls. We hypothesize that patients who develop ARIA will have higher IFSH scores than non-ARIA patients and healthy controls.

METHODS: Eligible AD patients who received anti-amyloid treatment were included in our retrospectively collected dataset. Only scans performed at 3T were used. Inter-rater reliability was evaluated and statistical analyses of IFSH scores and demographic data were performed to compare between groups. Additionally, within-subject analysis was used to compare the baseline and ARIA scans. Significance set at P < 0.05.

RESULTS: A total of 104 patients were selected based on the study criteria, of whom 60 had a clinical diagnosis of dementia. 36 patients developed ARIA, while 24 did not develop ARIA. 23 were age-matched healthy controls, and 21 were young healthy controls. Inter-rater reliability between the two readers was concordant when using quadratic weights appropriate for ordinal data (κ (w) = 0. 91, 95% CI 0.86-0.95). IFSH was significantly higher in the older age cohorts compared to young healthy controls (median 3.5 [IQR 2.5-5] versus 0 [0-1], P<0.001), with no significant difference between the dementia and healthy elderly groups (3.25 [3-4.875] versus 3.5 [2.5-5]). Among dementia patients on anti-amyloid therapy, significantly higher IFSH was observed in ARIA patients (at time of ARIA scan) compared to their non-ARIA counterparts (3.75 [3-5] versus 3 [2-4], P= 0.04). There was no significant difference in IFSH score between baseline and ARIA scans (P = 0.16).

CONCLUSION: IFSH was higher among dementia patients on anti-amyloid therapy with ARIA than among their non-ARIA counterparts. This supports its role as a potential biomarker of glymphatic dysfunction, although its utility on an individual basis is limited. Future prospective studies could benefit from incorporating IFSH as a variable, particularly if glymphatic therapies become a reality.},
}

@article {pmid42098313,
year = {2026},
author = {Shinagawa, S and Onuki, K and Shimizu, K},
title = {Physicians' perceptions and treatment practices for agitation associated with Alzheimer's dementia vary by specialty in Japan.},
journal = {Scientific reports},
volume = {},
number = {},
pages = {},
doi = {10.1038/s41598-026-51118-5},
pmid = {42098313},
issn = {2045-2322},
support = {NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; NA//Otsuka Pharmaceutical Co., Ltd./ ; },
abstract = {Agitation, a behavioural and psychological symptom of dementia, is under-recognized in Japan. To describe the physician's perceptions and treatment practice for agitation in Alzheimer's dementia (AAD) in Japan, we conducted a cross-sectional web-based survey in October 2024. The survey included physicians in neurology, neurosurgery, psychiatry, or general internal medicine who were registered with the survey panel; consented to participation; affiliated with hospitals or clinics; treating ≥ 10 people with Alzheimer's dementia (AD)/month. Responses from 529 physicians showed that they treated an average of 35.0 people with AD per month, of whom 8.4 (24%) had AAD. When asked what "agitation" brought to mind, physicians most commonly selected the Japanese term for "excitability", corresponding to the "agitation/aggression" item in the Neuropsychiatric Inventory (58.6%). In general internal medicine, 24.2% were unaware of agitation. Anti-dementia drugs (91.7%) were most frequently selected as new medications for AD, whereas in psychiatry, antipsychotics were most frequently selected (95.8%), and side effects were cited more often as a key consideration than in other specialties. These results suggest that perceptions and treatment practices vary by specialty, particularly reflected in common antipsychotic prescriptions with higher safety awareness among psychiatrists and limited recognition of AAD in others, especially in general internal medicine.},
}

@article {pmid42098771,
year = {2026},
author = {Badot, C and Bini, A and Duplan, E and Checler, F and Lauritzen, I},
title = {Functional relationships linking C99/APP-βCTF dimerization, proteostasis disruption, and organelle dysfunction.},
journal = {Cell communication and signaling : CCS},
volume = {},
number = {},
pages = {},
doi = {10.1186/s12964-026-02928-7},
pmid = {42098771},
issn = {1478-811X},
abstract = {BACKGROUND: The amyloid β (Aβ) precursor C99 (or APP-βCTF) accumulates in Alzheimer's disease and has been proposed to display Aβ-independent toxicity, notably by affecting the endosomal-lysosomal-autophagic (ELA) network. Our previous findings suggested that some ELA-associated C99 could correspond to dimeric and oligomeric species, but the intracellular sites of C99 dimerization, as well as the toxicity linked to it, remains unknown.

METHODS: We here developed a bimolecular fluorescence complementation (BiFC) probe to visualize de novo C99 dimerization and dimer trafficking, as well as to identify possible cellular responses specifically linked to C99 dimerization. Moreover, to confirm dimer localizations and toxicities, the localization and cellular effects of the dimerization mutant C99[G29L/G33L] was compared to that of wildtype C99. The C99 constructs were transfected into HeLa cells and dimer localizations, expression levels and intracellular toxicities were evaluated by Western blot and immunocytochemistry.

RESULTS: BiFC-C99 dimers were first detected within the TGN, in which monomers initially accumulate. The proteasomal inhibitor MG-132 led to increased dimer formation, indicating that the proteasomal activity status is a key determinant of C99 dimerization. Conversely, TGN-associated C99 dimerization had a negative impact on both the ubiquitin-proteasome system (UPS) and the TGN, as highlighted by the appearance of p62/SQSTM1-positive aggresomes and fragmented Golgi, then suggesting a two-way relationship between UPS function and C99 dimerization. Dimerization also led to lysosome repositioning and to the accumulation of LC3B-positive autophagy vesicles, agreeing with the well-known interplay between autophagy and proteasome in protein turnover. P62/SQSTM1 and LC3B accumulation could similarly be observed in cells expressing C99[G29L/G33L], a mutant favoring dimerization, while this was not the case in wildtype C99 expressing cells, confirming the dimerization-specific effect. While proteasomal inhibition caused TGN-associated dimer formation, repression of γ-secretase-mediated C99 proteolysis instead led to a redistribution of monomers to EEA1-positive endosomes, whereas already existing C99 dimers remained unaffected by this treatment. These new endosome-associated monomers were found also to dimerize, resulting in dimers destined for either secretion via small extracellular vesicles or autophagy-lysosomal degradation.

CONCLUSIONS: Taken together, our findings indicate that the cellular status of UPS, autophagy and γ-secretase activities are all determinant for C99 expression levels, and are thus crucial for both the level of C99 dimerization and for the fate of the dimers. Moreover, our data show that C99 dimerization itself negatively affects these activities thereby indicating a two-way relationship between C99 dimerization, proteostasis disruption and organelle dysfunction.},
}

@article {pmid42099124,
year = {2026},
author = {Cheng, B and Wei, W and Cheng, S and Yang, X and Pan, C and He, D and Feng, J and Zhang, F},
title = {Dynamic comorbidity trajectories spanning the diagnosis of depression: nationwide cohort study.},
journal = {The British journal of psychiatry : the journal of mental science},
volume = {},
number = {},
pages = {1-8},
doi = {10.1192/bjp.2026.10638},
pmid = {42099124},
issn = {1472-1465},
abstract = {BACKGROUND: Depression is often accompanied by multisystem comorbidities, but the time trajectories of these comorbidities remain unclear.

AIMS: We aimed to define the temporal sequence of comorbidity accrual relative to depression diagnosis, and examine how this trajectory differs in recurrent depression.

METHOD: A total of 32 953 individuals with depression were identified in the UK Biobank cohort, including 2402 with recurrent depression. The time between diagnosis of depression or recurrent depression and ten common comorbidities was established to determine the temporal order and rate of comorbidity diagnosis in relation to depression, based on the sequence of recorded diagnostic events. We further stratified the cohort by polygenic risk score, gender, age and history of antidepressant or antihypertensive medication use.

RESULTS: The study included 32 953 participants (mean age at diagnosis 52.6 years; 63.1% female). Hypertension and dorsopathies preceded depression diagnosis by a median of 2.6 years (interquartile range (IQR) -7.0 to 0.0) and 1.0 year (IQR -5.0 to 2.0), respectively. Alzheimer's disease and obesity emerged after diagnosis at medians of 2.5 years (IQR 0.0-5.0) and 0.8 years (IQR -2.0 to 3.0). High genetic risk was associated with an earlier onset of pre-depression cardiometabolic conditions, with hypertension occurring 2.8 years before diagnosis in individuals with a high polygenic risk score compared with 2.3 years in individuals with a low polygenic risk score. Crucially, individuals with recurrent depression exhibited a profoundly different trajectory, with most comorbidities manifesting many years after the index diagnosis. Stratification by medication history indicated that antihypertensive drug use was associated with an earlier recorded diagnosis of cardiometabolic conditions, whereas antidepressant use was linked to a later diagnosis of neurodegenerative diseases.

CONCLUSIONS: These findings identify three critical windows for intervention and reveal a distinct, delayed comorbidity trajectory in recurrent depression. This underscores the need for long-term, integrated surveillance strategies tailored to depression subtype and treatment history.},
}

@article {pmid42099163,
year = {2026},
author = {Li, Y and Li, L and Yang, Q and Xiong, J},
title = {Comparative Efficacy and Safety of Cholinesterase Inhibitors and NMDA Receptor Antagonists in Alzheimer's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050437623260417063631},
pmid = {42099163},
issn = {1875-5828},
abstract = {INTRODUCTION: The study aims to evaluate and rank cholinesterase inhibitors, the NMDA antagonist memantine, anti-amyloid monoclonal antibodies, and non-drug modalities with respect to cognitive outcomes, functional status, neuropsychiatric symptoms, and tolerability.

METHODOLOGY: We registered a protocol in PROSPERO and searched PubMed/MEDLINE, Embase, CENTRAL, Web of Science, trial registries, and gray literature through June 2025. Eligible randomized phase II/III trials in adults with clinically diagnosed AD were screened in duplicate. Data on interventions, comparators, outcomes (e.g., MMSE, ADAS-Cog, CDR-SB), and adverse events were extracted. Risk of bias was assessed using Cochrane RoB 2. A Bayesian random-effects NMA synthesized 125 trials (n > 30,000), estimating standardized Mean Differences (SMDs) with 95% Credible Intervals (CrIs). Heterogeneity (I²) and inconsistency (design-by-treatment, node-splitting) were evaluated.

RESULTS: The network was well connected, with low-to-moderate heterogeneity (global I² = 38.5%) and no significant inconsistency (p = 0.48). Cognitive training (SMD = 0.45; 95% CrI 0.30-0.60; SUCRA 92%), aerobic exercise (SMD = 0.55; 95% CrI 0.35-0.75; SUCRA 87%), and galantamine (SMD = 0.40; 95% CrI 0.22-0.58; SUCRA 84%) ranked highest versus placebo. Donepezil (SMD = 0.21; 95% CrI 0.11-0.30; SUCRA 78%) and memantine (SMD = 0.24; 95% CrI 0.13-0.35; SUCRA 72%) showed modest benefits.

DISCUSSION: Risk-of-bias ratings were low in 37% of trials, some concerns in 48%, and high in 15%. Subgroup analyses confirmed greater cholinesterase inhibitor efficacy in mild AD and superior memantine effects in moderate-to-severe disease.

CONCLUSION: Non-pharmacological interventions demonstrated short-term cognitive benefits primarily in mild Alzheimer's disease populations and should be interpreted as adjunctive symptomatic strategies rather than direct substitutes for pharmacological therapy.},
}

@article {pmid42099165,
year = {2026},
author = {Yang, Y and Huang, X and Liu, H and Yu, C},
title = {The Role of Ectopic Fat in Alzheimer's Disease.},
journal = {Current Alzheimer research},
volume = {},
number = {},
pages = {},
doi = {10.2174/0115672050461650260406064722},
pmid = {42099165},
issn = {1875-5828},
abstract = {Alzheimer's Disease (AD) is a neurodegenerative disorder increasingly recognized to be associated with metabolic dysfunction. Accumulating evidence suggests that ectopic fat (abnormal fat deposition in non-adipose tissue) is a key factor. This review summarizes the crucial role that ectopic fat plays in the onset and progression of AD, as well as the interrelated pathways through which ectopic fat deposition promotes the pathological process of AD. Adipocytes have been reported to produce and secrete amyloid-β (Aβ), a hallmark pathological feature of AD. Accordingly, ectopic fat may aggravate cerebral Aβ accumulation by impairing peripheral Aβ clearance. In addition, ectopic fat can also cause Insulin Resistance (IR), adipokine dysregulation, inflammatory responses, and oxidative stress. Therefore, ectopic fat is closely associated with the progression of AD and may play a contributory role in its pathogenesis. The effects of ectopic fat on the occurrence and development of Alzheimer's Disease (AD) pathology were reviewed through mechanisms such as metabolic disorders, inflammatory pathways, and Aβ deposition, and potential intervention strategies for this harmful cycle were highlighted. As current therapies for AD remain limited, new opportunities for its prevention and treatment may be provided through a better understanding of these associations.},
}

@article {pmid42100482,
year = {2026},
author = {Zhao, H and Wang, H and Li, W and Su, R and Li, J and Liu, Y and Wang, L},
title = {Integrated transcriptomic profiling combined with in vitro validation reveals the involvement of TMEM140 in the link between periodontitis and brain aging.},
journal = {Frontiers in aging neuroscience},
volume = {18},
number = {},
pages = {1761218},
pmid = {42100482},
issn = {1663-4365},
abstract = {OBJECTIVE: Periodontitis (PD) is a prevalent chronic inflammatory disorder in adults, and moderate-to-severe PD (Stage II-III/IV) may accelerate brain aging and neurodegenerative changes via the peripheral-central immune-neural axis, although the molecular connections and mechanisms of interaction have yet to be fully elucidated. This study sought to identify senescence-associated molecules potentially shared by PD and Alzheimer's disease (AD) using integrated transcriptomic analysis, machine learning, and in vitro RNA interference assays, and to further assess the role of TMEM140 in linking PD to brain aging.

METHODS: Transcriptomic datasets related to PD and AD were retrieved from the GEO database, and differential gene expression analysis was performed following batch effect correction; shared aging-associated genes were subsequently identified by combining weighted gene co-expression network analysis (WGCNA) with aging gene databases (HAGR and aging Atlas). Four machine learning algorithms, namely random forest (RF), support vector machine (SVM), generalized linear model (GLM), and extreme gradient boosting (XGB), were further applied to identify key genes, and their diagnostic value was assessed using receiver operating characteristic (ROC) analysis and nomogram models. DSigDB was used to predict candidate small-molecule compounds. In the in vitro experiments, a Porphyromonas gingivalis lipopolysaccharide (PG-LPS)-induced inflammatory model in human gingival fibroblasts (HGFs) and an Aβ1-42 and D-galactose-induced senescence model in SH-SY5Y neuron-like cells were established; TMEM140 in SH-SY5Y cells was then silenced using small interfering RNA (siRNA), and the neuron-like cells were treated with the same batch of standardized conditioned medium (CM; prepared from the supernatant of PG-LPS-treated HGFs) to observe changes in cellular responses to inflammatory stimulation after TMEM140 downregulation.

RESULTS: Seven aging-related genes common to PD and AD were identified, and comprehensive analysis using multiple algorithms selected TMEM140, TIMP1, and ALDH2 as key genes. Notably, TMEM140 was upregulated in PD and downregulated in AD, showed significant correlations with plasma cell and γδ T-cell infiltration, and single-cell analysis further revealed its cell type-specific expression in distinct brain cell subsets. In vitro experiments demonstrated that PG-LPS treatment markedly increased TMEM140 expression in HGFs, whereas treatment with Aβ1-42 and D-galactose reduced TMEM140 expression in neuron-like cells. When exposed to the same batch of conditioned medium, neuron-like cells with TMEM140 knockdown displayed more evident injury and senescence-related phenotypes, including reduced cell viability, increased reactive oxygen species (ROS) production, a higher percentage of senescence-associated β-galactosidase (SA-β-Gal)-positive cells, and marked upregulation of IL-1β, IL-6, TNF-α, p16, p21, RELA, NFKBIA, and TP53, indicating that reduced TMEM140 expression may contribute to enhanced susceptibility of neuron-like cells to inflammatory stress.

CONCLUSION: Through integrated transcriptomic analysis together with in vitro experimental validation, this study indicates that TMEM140 may be a candidate bridge molecule connecting PD and AD comorbidity. TMEM140 may participate in shaping the peripheral-central immunosenescence network and contribute to the cross-system transmission of inflammatory signaling.},
}

@article {pmid41896988,
year = {2026},
author = {Ma, Y and Xie, M and Ibáñez, CF},
title = {Palmitoylation of death receptor p75[NTR] contributes to Alzheimer's disease progression by regulating APP trafficking and degradation.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41896988},
issn = {1758-9193},
abstract = {UNLABELLED: Although protein palmitoylation has been associated with Alzheimer’s Disease (AD), it remains unclear whether or how palmitoylation of specific proteins contributes to any of the pathological features of AD. The p75 neurotrophin receptor (p75[NTR]) contributes to AD progression by regulating the intracellular trafficking and amyloidogenic processing of amyloid precursor protein (APP). p75[NTR] is palmitoylated at a juxtamembrane cysteine but it is currently unknown whether this has any effect on its role in AD. Here, we report that 5xFAD mice, an animal model of AD, expressing a palmitoylation-deficient mutant of p75[NTR] (p75[C281A]) display significantly attenuated neuropathology and cognitive deficits. Mechanistically, p75[C281A] showed enhanced internalization, trafficking to Rab5/Rab7 endosomes and lysosomal-mediated degradation. In mutant p75[C281A] neurons, APP displayed accelerated co-internalization with p75[NTR], increased trafficking to late endosomes and lysosome, and enhanced degradation, thereby limiting neuronal Aβ production. Interestingly, the brain of 5xFAD mice shows increased levels of p75[NTR] palmitoylation. These results indicate that palmitoylation of p75[NTR] enhances its stability and, indirectly, that of APP by reducing their trafficking to the lysosome, resulting in increased Aβ accumulation and neuropathology in the AD brain. Selective inhibitors of p75[NTR] palmitoylation may find applications in the treatment of AD.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02032-5.},
}

@article {pmid41896998,
year = {2026},
author = {van der Schaar, J and van der Flier, WM and Visser, LNC and van de Giessen, E and van Harten, AC and Sikkes, SAM and van Leeuwenstijn-Koopman, MSSA and Hendriksen, HMA and Trieu, C and Bredenoord, AL and van den Hoven, MA and Asscher, ECA},
title = {Long-term impact of disclosing amyloid PET results to individuals with subjective cognitive decline.},
journal = {Alzheimer's research & therapy},
volume = {18},
number = {1},
pages = {},
pmid = {41896998},
issn = {1758-9193},
support = {LSHM20106//Health∼Holland, Topsector Life Sciences & Health/ ; LSHM20106//∼Holland, Topsector Life Sciences & Health/ ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; 73305095007/ZONMW_/ZonMw/Netherlands ; },
abstract = {BACKGROUND: Biomarker assessments increasingly inform the diagnostic evaluation and treatment decisions in Alzheimer disease (AD). However, evidence on the impact of amyloid positron emission tomography (PET) disclosure is primarily derived from studies of cognitively unimpaired trial participants with follow-up limited to 18 months. In contrast, long-term implications for individuals with cognitive concerns who seek medical evaluation in memory clinics remain unknown. We aimed to examine the psychosocial and behavioral impact three years after amyloid PET disclosure in individuals presenting with subjective cognitive decline (SCD) at a memory clinic.

METHODS: In-depth semi-structured interviews were conducted with 17 participants from the Subjective Cognitive Impairment Cohort (SCIENCe) (67 ± 7 years; 5 female; 10 amyloid positive) 35 ± 4 months post-disclosure. All had SCD at imaging; one had progressed to mild cognitive impairment (MCI) at interview. Verbatim transcripts were analyzed inductively.

RESULTS: Participants’ motivations for testing and long-term adaptation to the results were strongly shaped by cognitive concerns and personal experiences of dementia in relatives. All demonstrated accurate comprehension of their amyloid status. Those with negative scans described immediate relief and reattributed memory lapses to normal aging, while recognizing that the reassurance was provisional. Although positive scans provoked initial shock and fear of deterioration, participants valued information over uncertainty, and over time, fear attenuated as they perceived no rapid decline. Both groups regarded results as meaningful and personally actionable, informing health behavior, life priorities, and preparations for future decline. Fourteen of 17 participants spontaneously mentioned considering options for self-determined end-of-life. Regardless of amyloid status, most participants shared their result with close relatives and friends, some also informed colleagues or acquaintances, while others limited communication to avoid stigma, protect loved ones, or reduce the burden of repeated explanations. Participants valued testing, expressed no regret, and would choose disclosure again.

CONCLUSIONS: Three years after disclosure, participants generally had adjusted to living with their imaging result, finding personal meaning and practical engagement without reporting ongoing psychological harm. Some reported residual concerns and uncertainty, irrespective of amyloid status. These findings offer timely guidance for clinicians and patients as biomarker disclosure is more widely incorporated into routine practice.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13195-026-02026-3.},
}

@article {pmid42089987,
year = {2026},
author = {Chen, S and Zhao, K and Shi, Z and Zhang, C and Wu, H and Tian, M and Sun, Y and He, L},
title = {Study on the improvement effect and mechanism of resveratrol on cognitive impairment in tau mutant adenovirus-induced alzheimer's disease model mice.},
journal = {Psychopharmacology},
volume = {},
number = {},
pages = {},
pmid = {42089987},
issn = {1432-2072},
abstract = {RATIONALE: Tau protein hyperphosphorylation and neuroinflammation playimportant roles in the onset and progression of Alzheimer's disease (AD). SIRT1has been implicated in the regulation of synaptic plasticity, cognitive function, andmemory, and is associated with the modulation of autophagy-and inflammation-related signaling pathways, including AMPK/mTOR/ULK1 and NF-κB. Resveratrol(RSV) has been reported to ameliorate cognitive impairment in AD models,primarily in the context of Aβ-related pathology; however, its potential effects andunderlying mechanisms in Tau-driven pathology remain incompletely understood.

OBJECTIVES: To investigate the effect of RSV on cognitive impairment in mice withTau mutation-induced Alzheimer's disease, and to explore its effects on autophagyand neuroinflammation.

METHODS: Tauopathy models were established using AAV-P301L-Tau. Cognitivefunction was assessed via behavioral tests; Hippocampal injury was evaluatedAccepted manuscriptACCEPTED MANUSCRIPTusing HE and Nissl staining, while autophagy was assessed byimmunofluorescence staining. Mechanisms were examined using Western blot,qRT-PCR, and CCK-8 assays.

RESULTS: RSV treatment was associated with attenuation of neuronal damage,reduction of p-Tau accumulation, and improvement of cognitive impairment in ADmice. Consistent trends were observed in vitro, where RSV treatment wasassociated with increased cell viability and modulation of autophagy-relatedmarkers in AAV-P301L-Tau-induced BV2 cells. In addition, RSV administration wasaccompanied by coordinated changes in signaling components related to SIRT1,AMPK/mTOR/ULK1, and NF-κB pathways, along with reduced expression ofinflammatory mediators.

CONCLUSIONS: RSV treatment was associated with coordinated modulation ofsignaling components related to the AMPK/mTOR/ULK1 and NF-κB pathways,together with improvements in cognitive performance in AD mice. These findingssupport the potential therapeutic relevance of RSV in Tau-drivenneurodegenerative pathology, while further studies are required to clarify theunderlying mechanisms.},
}

@article {pmid42090736,
year = {2026},
author = {Malotaux, V and Ku, V and Ospina Lopera, P and Su, Y and Chen, Y and Singh, A and Ruiz-Triviño, J and Hidalgo, MJ and Osorio, L and Serna, L and Giraldo, D and Alzate, D and He, B and Tristão-Pereira, C and Ramirez Gomez, L and Do Carmo, S and Cuello, AC and Ashton, NJ and Reiman, EM and Aguillón, D and Quiroz, YT},
title = {Associations of plasma biomarkers with age in the presenilin-1 E280A autosomal dominant Alzheimer's disease kindred.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {6},
pages = {100578},
doi = {10.1016/j.tjpad.2026.100578},
pmid = {42090736},
issn = {2426-0266},
abstract = {BACKGROUND: Autosomal-dominant Alzheimer's disease (ADAD) offers a model to define early biological changes in Alzheimer's disease due to its predictable age at symptom onset. Although ultrasensitive plasma assays are available, their associations with age in ADAD remain incompletely characterized.

OBJECTIVES: To characterize age-related changes in plasma biomarkers and examine associations with cognition in PSEN1 E280A ADAD.

DESIGN AND SETTING: Cross-sectional observational study in members of the Colombian PSEN1 E280A kindred.

PARTICIPANTS: A total of 164 individuals were included, comprising 83 mutation carriers (mean age 34.36±9.82 years; 54% female) and 81 non-carriers (mean age 33.75±9.84 years; 52% female).

MEASUREMENTS: Plasma Aβ42/Aβ40, phospho-tau217 (p-tau217), brain-derived tau (BD-tau), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were quantified. Sex-adjusted associations with age, divergence ages between groups, classification performance (ROC curves), and associations with cognition (MMSE and CERAD delayed recall) were assessed.

RESULTS: All plasma biomarkers were associated with age (p < .01). Divergence between carriers and non-carriers began with Aβ42/Aβ40 before age 18, followed by p-tau217 (26.0 years), GFAP (26.1 years), BD-tau (27.9 years), and NfL (38.7 years). Aβ42/Aβ40 showed the highest discrimination of mutation status (AUC=0.99), followed by p-tau217 (AUC=0.87) and GFAP (AUC=0.84). Among carriers, p-tau217, GFAP, BD-tau, and NfL were associated with MMSE, while p-tau217, GFAP, and NfL predicted CERAD delayed recall.

CONCLUSION: Plasma biomarkers exhibit a temporal cascade in PSEN1 E280A ADAD. P-tau217 and GFAP show the strongest associations with early cognitive decline, suggesting their potential utility for tracking disease progression and monitoring treatment effects in E280A carriers.},
}

@article {pmid42090785,
year = {2026},
author = {Sánchez Valle, R and Lleó Bisa, A and Villarejo Galende, A and Cuartero Rodríguez, E and Escudero-Torrella, J and Bargallo Alabart, N},
title = {Adapting the spanish healthcare system for disease-modifying treatments in early-stage alzheimer's disease.},
journal = {The journal of prevention of Alzheimer's disease},
volume = {13},
number = {7},
pages = {100586},
doi = {10.1016/j.tjpad.2026.100586},
pmid = {42090785},
issn = {2426-0266},
abstract = {BACKGROUND: The emergence of disease-modifying therapies targeting amyloid pathology represents a major paradigm shift in the management of Alzheimer disease (AD). However, their implementation poses substantial organizational, infrastructural, and clinical challenges for health systems.

OBJECTIVES: To identify the key challenges and establish priority recommendations for the effective incorporation of amyloid-targeting therapies into the Spanish National Health System.

This multiphase consensus study was conducted within the Spanish National Health System between September 2024 and July 2025. The study comprised a narrative literature review, qualitative research, regional workshops, and a modified RAND/UCLA Delphi process. A total of 56 experts participated, including a scientific committee of 6 Alzheimer disease specialists and an expert panel of 50 multidisciplinary professionals involved in AD care.

MEASUREMENTS: Identification of key challenges across the AD care pathway; development, evaluation, and prioritization of consensus-based recommendations; and estimation of patient demand, including projected increases in day hospital activity and magnetic resonance imaging utilization.

RESULTS: Ten key challenge areas were identified, encompassing early detection and referral, diagnostic confirmation, assessment of patient eligibility, treatment administration in day hospitals, monitoring of amyloid-related imaging abnormalities, evaluation of treatment effectiveness, infrastructure and capacity, professional training, patient information and support, and health care planning. Of the 43 recommendations assessed, 38 were rated as appropriate and necessary, with 14 prioritized for immediate implementation. Demand estimation models indicated that 11 to 26 patients per 100,000 inhabitants could be treated under current care patterns, increasing to 17 to 115 per 100,000 inhabitants under alternative eligibility scenarios.

CONCLUSIONS: This consensus defines the clinical, organizational, and infrastructural requirements necessary to integrate amyloid-targeting therapies into routine care within the Spanish National Health System. The prioritized recommendations define immediate actions to address the challenges identified and may serve as a reference for other health systems facing similar implementation processes.},
}

@article {pmid42091766,
year = {2026},
author = {Kumar, V and Kakoty, V and Wadhwa, P},
title = {Advancements in Gene Delivery using Nucleic Acid Loaded Nanoparticles for Region Specific Delivery in Alzheimer's Disease.},
journal = {Molecular neurobiology},
volume = {63},
number = {1},
pages = {},
pmid = {42091766},
issn = {1559-1182},
mesh = {*Alzheimer Disease/therapy/genetics ; *Nanoparticles/chemistry/administration & dosage ; Humans ; *Gene Transfer Techniques ; Animals ; *Nucleic Acids/administration & dosage ; *Genetic Therapy/methods ; Brain/metabolism ; },
abstract = {Alzheimer's disease (AD) is a progressive and the most common neurodegenerative condition, having a deleterious effect on memory, eventually leading to death. In the recent past, gene therapy has emerged as a promising and revolutionary treatment for AD. This study demonstrated that nucleic acid-loaded nanoparticles which deliver small interfering RNA through lipid nanoparticles successfully reduced Alzheimer's disease-related symptoms in preclinical models by decreasing amyloid-β levels and enhancing cognitive abilities. However, every rose has its thorn, as the output of gene therapy is considerably hampered by the physiological barriers of the brain, which include the blood-brain barrier and the brain's extracellular matrix (ECM). For this reason, many researchers have modified the gene delivery technique by developing 'brain penetrating' NPs coated with components that can prevent sticking to the ECM. Moreover, to overcome the challenge of low transgene expression and reduced accumulation in the brain, even when delivered at high doses, scientists have proposed that injection/delivery of gene vectors directly into a specific area in the brain can achieve maximum therapeutic efficacy. Hence, this review focuses on the advancements and advantages of region-specific delivery of nucleic acid-loaded NPs for the effective therapeutic management of AD.},
}

*Alzheimer Disease/therapy/genetics
*Nanoparticles/chemistry/administration & dosage
Humans
*Gene Transfer Techniques
Animals
*Nucleic Acids/administration & dosage
*Genetic Therapy/methods
Brain/metabolism

@article {pmid42091792,
year = {2026},
author = {Otaegui, L and Lehoux, J and Begu, S and Moujellil-Legagneur, T and Zussy, C and Vitalis, M and Mathias, M and Beau, A and Durand, T and Givalois, L and Bernoud-Hubac, N and Crauste, C and Desrumaux, C},
title = {Intranasal lipid nanocapsule administration of the new lipophenol quercetin-3-O-DHA-7-O-iPr reduces carbonyl stress and improves behavior in a mouse model of Alzheimer's disease.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42091792},
issn = {2190-3948},
support = {CBS2 PhD grant//Université Montpellier/ ; MUSE-AAP20REC-FRS09-GAiA//Université Montpellier/ ; PhD grant//Association France Alzheimer/ ; ANR-AAP2022-R22102FF-EpiNeurAge//Agence Nationale de la Recherche/ ; ANR-18-CE18-0017//Agence Nationale de la Recherche/ ; ANR-11-LABEX-0021-LipSTIC//Agence Nationale de la Recherche/ ; MND202003011477-OPA//Fondation pour la Recherche Médicale/ ; },
abstract = {Oxidative and carbonyl stresses (COS), which damage brain cells through the accumulation of toxic reactive carbonyl species (RCS), are key players in the etiology of Alzheimer's disease (AD). Our group developed lipophenols, i.e. COS-targeting hybrid molecules combining polyunsaturated fatty acids (PUFAs) and alkyl-(poly)phenols. Among them, quercetin-3-O-docosahexaenoate-7-O-isopropyl (Quercetin-3-O-DHA-7-O-iPr or "Q-iP-DHA") afforded neuroprotection against acrolein-induced toxicity, reduced carbonyl stress, and lowered amyloid-beta secretion in neuroblastoma cells. To evaluate Q-iP-DHA in vivo, it was formulated into lipid nanocapsules (to allow solubilization) then administered intranasally to J20 transgenic mice, a model of AD. This approach was chosen to optimize blood-brain barrier (BBB) penetration. This delivery led to improvements in well-being, organizational skills and spatial memory. In addition, Q-iP-DHA treatment reduced hippocampal amyloid plaque numbers, normalized expression of the Receptor for Advanced Glycation End-products (RAGE), and decreased microglial activation, indicating anti-inflammatory effects. Overall, our preclinical findings suggest that intranasal administration of nanoformulated Q-iP-DHA may represent a promising multitarget therapeutic approach against AD.},
}

@article {pmid42093461,
year = {2026},
author = {Andreão, FF and da Silva, RO and Negreli, MFLA and Aguiar-Barros, ABP and Santos, DH},
title = {Baseline epidemiological differences between donanemab and lecanemab users in real-world settings: a retrospective cohort study.},
journal = {Neurodegenerative disease management},
volume = {},
number = {},
pages = {1-6},
doi = {10.1080/17582024.2026.2667432},
pmid = {42093461},
issn = {1758-2032},
abstract = {AIMS: Donanemab and Lecanemab are anti-amyloid monoclonal antibodies recently approved for the treatment of Alzheimer's disease. Although their efficacy and safety have been investigated in randomized trials, real-world epidemiological data on treated populations remain limited. This study aimed to compare baseline clinical and laboratory characteristics of patients treated with donanemab versus lecanemab in routine practice.

PATIENTS AND METHODS: We conducted a retrospective analysis using the TriNetX US Collaborative Network, including patients with Alzheimer's disease treated with donanemab or lecanemab between January 2024 and September 2025. Demographics, laboratory values, comorbidities, and concomitant medications were compared using standardized mean differences (SMD) and p-values. Variables with SMD ≥0.1 or p < 0.05 were considered meaningfully different.

RESULTS: A total of 1,799 patients were included (donanemab n = 360; lecanemab n = 1,439). Demographic characteristics were well balanced (mean age 73.1 vs 72.5 years; SMD 0.028). Lecanemab users were more likely to be prescribed antidepressants (52% vs 41%; p < 0.0001; SMD = 0.23) and donepezil (61% vs 52%; p = 0.0145; SMD = 0.14). Donanemab users had higher prothrombin time (12.2 ± 2.17 vs 11.8 ± 1.66 s; p = 0.0158; SMD = 0.20) and INR (1.06 ± 0.19 vs 1.03 ± 0.13; p = 0.0369; SMD = 0.17), and a higher prevalence of vascular dementia (81% vs 76%; p = 0.0272; SMD = 0.12).

CONCLUSION: While demographic variables were similar. These findings likely reflect real-world clinical selection patterns and should be accounted for in comparative effectiveness and safety analyses of anti-amyloid therapies.},
}

@article {pmid42094385,
year = {2026},
author = {Sanders, B and Korthauer, M and Singh Parihar, K and Ifergan, I},
title = {Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles attenuate neuroinflammation and Alzheimer's disease-related pathology in 5xFAD mice.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.27.720934},
pmid = {42094385},
issn = {2692-8205},
abstract = {Alzheimer's disease is characterized by progressive cognitive decline, amyloid-β deposition, neuroinflammation, and neurodegeneration, yet effective and well-tolerated therapies remain limited. Because dysregulated myeloid responses are increasingly recognized as important drivers of disease progression, we investigated the therapeutic potential of poly(lactic-co-glycolic acid) immunomodulatory nanoparticles in the 5xFAD mouse model of amyloid-driven neurodegeneration. Poly(lactic-co-glycolic acid) immunomodulatory nanoparticles and fluorescently labeled particles displayed the expected size range and negative surface charge. After intraperitoneal administration, fluorescent particles were preferentially associated with myeloid cells in the blood, spleen, and brain, with greater uptake by brain myeloid populations in 5xFAD mice than in wild-type controls. Therapeutic treatment of 6.5-month-old 5xFAD mice, a stage at which behavioral abnormalities are already established, resulted in significant improvement in elevated plus maze behavior and a more modest improvement in Barnes maze performance. Flow cytometric analysis performed 9 weeks after the final treatment demonstrated persistent changes in brain immune composition, with the most prominent effects observed in P2RY12 [+] microglial populations, particularly the CD11c [+] subset, and comparatively limited sustained effects in CD11b [+] P2RY12 [-] myeloid cells. These changes were accompanied by reduced expression of activation- and disease-associated markers and lower pro-inflammatory cytokine production within microglial populations. Histological analysis further showed reduced cortical amyloid plaque burden, decreased CD68 immunoreactivity, and reduced neurodegeneration in treated 5xFAD mice. Together, these findings show that systemically administered poly(lactic-co-glycolic acid) immunomodulatory nanoparticles produce durable behavioral, immunological, and pathological benefits in 5xFAD mice and support further investigation of this biodegradable myeloid-targeted platform as a therapeutic strategy for Alzheimer's disease.},
}

@article {pmid42094534,
year = {2026},
author = {Moore, SJ and Murphy, GG},
title = {Acarbose improves cognitive function in a mouse model of normal aging but not Alzheimer's disease.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.28.721469},
pmid = {42094534},
issn = {2692-8205},
abstract = {INTRODUCTION: Declines in function occur in both normal aging (in the absence of disease) and age-related pathological contexts, like Alzheimers disease (AD). Whether anti-aging interventions (that extend lifespan) also promote cognitive function in aging and AD remains unexplored.

METHODS: We assessed the effect of acarbose (1000 ppm from 4 months of age) on spatial learning and memory using the Morris water maze in young adult (6 mo), mid-aged (12 mo), or aged (24 mo) cohorts of normal aging (Ntg-HET3) and AD-relevant (5xFAD-HET3) genetically heterogeneous mice.

RESULTS: In mid-aged and aged Ntg-HET3 mice, acarbose treatment resulted in performance equivalent to young adults. Conversely, acarbose failed to ameliorate age-related deficits in 5xFAD-HET3 mice.

DISCUSSION: This work demonstrates that anti-aging interventions can also promote cognitive longevity in normal aging. Further, it reinforces that AD is not simply accelerated aging and requires therapies beyond anti-aging interventions that target its unique molecular and cellular drivers.},
}

@article {pmid42094538,
year = {2026},
author = {Woodham, TA and Kelsey, MMG and Sedivy, JM},
title = {Characterization of Cellular Senescence in Primary Human Astrocytes.},
journal = {bioRxiv : the preprint server for biology},
volume = {},
number = {},
pages = {},
doi = {10.64898/2026.04.29.721581},
pmid = {42094538},
issn = {2692-8205},
abstract = {Senescent astrocytes have been identified in the brains of patients with neurodegenerative disorders, including Alzheimer's disease, yet the molecular characteristics of replicative senescence in human astrocytes remain largely unexplored. Prior work has been hampered by the low proliferative capacity and limited telomere shortening of primary human astrocytes in culture. Here, we describe a culture system in which primary human astrocytes propagated under physiological (3%) oxygen reach canonical telomeric replicative senescence after extensive expansion (up to ~76 population doublings). Senescence was confirmed through multiple biomarkers, including reduced EdU incorporation, elevated senescence-associated beta-galactosidase (SA-β-gal) activity, persistent DNA damage foci (γH2AX and 53BP1) predominantly localized to telomeres, and nuclear accumulation of p53. RNA sequencing across a 12-week time course revealed early upregulation of young LINE-1 (L1HS) retrotransposon transcripts, type-I interferon (IFN-I) and senescence-associated secretory phenotype (SASP) pathway genes, alongside downregulation of cell-cycle and DNA repair programs. To resolve L1HS expression at individual locus resolution, we performed Nanopore DNA sequencing to generate a custom reference genome incorporating non-reference LINE-1 insertions. Applying our TE-Seq pipeline, we identified two full-length intergenic L1HS elements consistently upregulated across the replicative senescence time course, one of which, L1HS_9q22.32_2, retained intact ORF1 and ORF2 open reading frames, indicating potential retrotransposition competence. To contextualize the astrocyte replicative senescence program, we compared it to three additional conditions. First, parallel astrocyte cultures maintained under normoxic (20%) oxygen entered senescence earlier and showed stronger SASP upregulation. Second, DNA damage-induced senescence (DDIS) triggered by etoposide treatment produced a stronger pro-inflammatory transcriptional signature than replicative senescence, including elevated IL6, IL1A, and IL1B expression. DDIS also upregulated L1HS_9q22.32_2 as well as a second intact element, L1HS_14q23.2_3, which we have previously identified among the small number of intact L1HS loci activated during replicative senescence in fibroblasts. The convergent activation of these intact elements across cell types and senescence modalities reinforces L1HS-driven IFN-I signaling as a conserved feature of the senescent program. Third, comparison with replicatively senescent fibroblasts revealed cell-type-specific SASP regulation: the pro-inflammatory cytokines IL6 and CCL2 were downregulated in senescent astrocytes relative to proliferating cells, opposite to their behavior in fibroblasts. Together, these data establish the first comprehensive transcriptomic profile of replicative senescence in human astrocytes, offering a resource for understanding brain aging and senescence-associated neurodegeneration.},
}

@article {pmid42095064,
year = {2026},
author = {Cummings, JL and Zhou, Y and Yang, Y and Zhong, K and Fonseca, J and Osse, AL and Cheng, F},
title = {Alzheimer's disease drug development pipeline: 2026.},
journal = {Alzheimer's & dementia (New York, N. Y.)},
volume = {12},
number = {},
pages = {e70251},
pmid = {42095064},
issn = {2352-8737},
abstract = {INTRODUCTION: Discovery and development of new therapies for Alzheimer's disease (AD) are urgently needed to address the world's growing population of individuals on the AD pathophysiological continuum. Clinicaltrials.gov is a resource for studying drugs in development for treatment of AD.

RESULTS: There are currently 158 drugs in 192 AD trials. Of the agents in trials, 39% are small molecule disease targeting therapies (DTTs); 34% are biologic DTTs; 18% are cognition enhancing symptom targeted therapies (STTs); and 10% are STTs being developed to treat neuropsychiatric symptoms of AD. Currently active trials require 54,728 participants of which 38,417 are in Phase 3. The biopharmaceutical industry sponsors 59% of AD trials including 72% of Phase 3 trials. Repurposed drugs represent 35% of the drugs in trials.

DISCUSSION: The AD drug development pipeline has a growing number of trials and drugs in trials. A diverse array of AD pathophysiological processes is being addressed by drugs in trials.},
}

@article {pmid42095076,
year = {2026},
author = {Sajan, MP and Aggarwal, G and Hwang, JJ and Smith, DM and Cooper, DR and Duncan, MA and Hansen, BC and Nguyen, AD and Farese, RV},
title = {Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.},
journal = {iScience},
volume = {29},
number = {5},
pages = {115720},
pmid = {42095076},
issn = {2589-0042},
abstract = {Molecular mechanisms in frontotemporal dementia (FTD) and Alzheimer's disease (AD) are obscure. FTD can result from loss-of-function progranulin mutations, although pathogenetic consequences are uncertain. Progranulin insufficiency also increases human AD risk, and progranulin treatment improves mouse AD. Furthermore, AD and FTD risks are abetted by obesity/diabetes-induced hyperinsulinemia and hyperactivation of brain insulin signaling, and progranulin deficiency activates insulin signaling in fat and liver. Here, we found progranulin deletion in mouse brain increased activation of IRS-1 and activities of downstream PKC-λ/ι, NF-κB and mTOR, but diminished IRS-2 and Akt. Similarly, in microglial cells, progranulin deletion increased, and progranulin treatment diminished, activation of IRS-1, PKC-λ/ι, NF-κB, and mTOR. These progranulin-related changes in IRS-1 activation were due to JNK-mediated phosphorylation of inhibitory serine-302/307 residues in IRS-1. Progranulin deficiency in brain selectively activates an IRS-1-dependent insulin signaling pathway, and the resultant increases in inflammation and impaired autophagy/lysosomal function may augment progranulin deficiency-related neuropathology.},
}

@article {pmid42095886,
year = {2026},
author = {Maiese, K},
title = {Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, wnt, and WISP1.},
journal = {Expert review of clinical pharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1080/17512433.2026.2671269},
pmid = {42095886},
issn = {1751-2441},
abstract = {INTRODUCTION: Increased global lifespan is paralleled by a rise in non-communicable diseases with osteoarthritis and dementia, including Alzheimer's disease, impacting all nations with severe disability, death, and financial burden.

AREAS COVERED: Given that osteoarthritis and dementia are worsened with advancing age, progressive in nature, and presently remain only with symptomatic treatments, development of advanced comprehensive therapies is critical for these disorders. New innovative work offers insight into the underlying clinical bond between degenerative joint disease and cognitive loss. Data sources using systematic literature search employed PubMed, Scopus, Web of Science, and ScienceDirect from January 2021 through February 2026.

EXPERT OPINION: Although affecting diverse organ systems, degenerative joint disease and dementia are intimately connected by shared cellular pathways responsible for disease onset and progression. Pioneering avenues of investigation of oxidative stress, autophagy, the mechanistic target of rapamycin (mTOR), cellular metabolism mechanisms with glucagon-like peptide-1 (GLP-1) receptors and AMP activated protein kinase (AMPK), Wnt signaling, and Wnt1 inducible signaling pathway protein 1 (WISP1) offer exciting treatment opportunities for osteoarthritis and Alzheimer's disease. Ultimately, these complex pathways will necessitate focus upon their intricate dependence that may benefit from several targeted approaches including artificial intelligence applications for fruitful clinical translation.},
}

@article {pmid42096531,
year = {2026},
author = {Uchida, H and Gobbi, G and Zohar, J and Young, AH and Rujescu, D and Huang, MC and Sundram, S and Atwoli, L and Vukovic, J and Ikeda, K},
title = {Global Perspectives on CNS Drug Innovation: Achievements, Barriers, and Priorities for the Next Decade.},
journal = {The international journal of neuropsychopharmacology},
volume = {},
number = {},
pages = {},
doi = {10.1093/ijnp/pyag023},
pmid = {42096531},
issn = {1469-5111},
abstract = {BACKGROUND: Over the past decade, neuropsychopharmacology has shifted from stagnation to momentum, with first-in-class mechanisms and biomarker-enabled trials spanning psychiatry and neurology.

METHODS: We narratively synthesized advances from 2013 to 2026 across central nervous system (CNS) discovery and development, including pivotal trials, regulatory actions, digital/real-world evidence, genetics, artificial intelligence (AI), and implementation/global-access themes that are endorsed by international societies.

RESULTS: Therapeutic gains include rapid-acting drugs for treatment-resistant depression (intranasal esketamine); psychedelic-assisted therapy for posttraumatic stress disorder and depression; neuroactive steroid γ-aminobutyric acid-A receptor positive allosteric modulators (brexanolone, zuranolone) for postpartum depression; non-dopaminergic muscarinic agonists (xanomeline-trospium) for schizophrenia; orexin receptor antagonists for insomnia; and anti-amyloid monoclonal antibodies (lecanemab, donanemab) for early Alzheimer's disease. Persistent barriers include high mid-/late-stage attrition that is driven by placebo effects, subjective endpoints, and preclinical-to-clinical gaps; regulatory and economic headwinds; and limited generalizability from tightly run trials. Emerging enablers include adaptive/platform designs, digital health technologies, patient-reported outcomes, and clinical outcome assessments, real-world evidence (RWE), AI/machine learning (ML), genetics for target de-risking and biomarker-guided stratification, and publicly accessible large CNS relevant biological datasets.

CONCLUSIONS: To convert momentum into durable progress, we recommend: (i) deeper academia-industry/stakeholder collaboration and sustained funding for high-risk/high-reward science from industry, governments and non-for profit foundations; (ii) modernized regulation (flexible evidentiary paths, novel endpoints, and clear guidance on adaptive/platform trials); (iii) data-driven development integrating RWE, AI/ML, and precision medicine; (iv) the adoption of Neuroscience-based Nomenclature (NbN); and (v) a global-access mandate with essential-medicine inclusion, equitable pricing/licensing, capacity building, tele-enabled mental health, and geographically diverse research. Aligning scientific innovation with implementation and equity can accelerate translation and ensure new treatments benefit patients worldwide.},
}

@article {pmid42097044,
year = {2026},
author = {Shu, Y and Ding, ZH and Chen, XQ and Liu, F},
title = {40 Hz light flicker stimulation for neurodegenerative diseases: Mechanisms and clinical perspectives.},
journal = {Biochemical and biophysical research communications},
volume = {821},
number = {},
pages = {153858},
doi = {10.1016/j.bbrc.2026.153858},
pmid = {42097044},
issn = {1090-2104},
abstract = {Neurodegenerative diseases are a class of disorders characterized by the progressive degeneration and dysfunction of neurons, such as Alzheimer's disease (AD) and Parkinson's disease (PD). Due to their high incidence rate, irreversible pathological processes and huge social and economic burdens, these diseases have become a major challenge in global public health. Light Flicker Stimulation (LFS), as a non-invasive form of physical therapy, shows significant neuroprotective potential by modulating electrical brain oscillations and particular signaling pathways. We critically examine the role of stimulation parameters (frequency, wavelength, multisensory combination) and discuss the state of clinical translation, including completed and ongoing trials, safety considerations, and technological innovations such as alternating bilateral stimulation and organic light-emitting diode (OLED) devices. By integrating mechanistic insights with clinical perspectives, this review aims to identify key gaps and future directions for harnessing 40 Hz LFS as a viable treatment for neurodegenerative diseases.},
}

@article {pmid42097270,
year = {2026},
author = {Cho, E and Lee, S and Lee, H and Kim, J and Kwon, YW and Hoe, HS and Kim, D and Yoon, JH},
title = {An integrative proteomic approach to reveal altered signaling modules during Alzheimer's disease progression in PS19 tauopathy mice.},
journal = {Molecular & cellular proteomics : MCP},
volume = {},
number = {},
pages = {101580},
doi = {10.1016/j.mcpro.2026.101580},
pmid = {42097270},
issn = {1535-9484},
abstract = {Alzheimer's disease (AD) is a slowly progressive neurodegenerative disease that is characterized by cognitive, functional, and behavioral impairments. These changes occur owing to the progressive accumulation of extracellular amyloid-beta plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is associated with the dysfunction of several essential neurotransmitter systems, such as dopamine, and impaired neurotransmission. Despite the association of neurotransmitter changes within the brain and AD pathology, in-depth profiling studies on neurotransmitters and their related proteomic changes are limited. This study was conducted to profile and integrate the proteomes and neurotransmitters in seven brain regions of PS19 (Tau P301S) mice according to AD progression between 4 and 7 months. Proteomic analysis revealed significantly altered canonical pathways in various brain regions, including metabolic abnormalities. In the neurotransmitter profile, we found significant alterations in the levels of six neurotransmitters-dopamine, serotonin, homovanillic acid, norepinephrine, 3-methoxytyramine, and 3,4-dihydroxyphenylacetic acid-during AD progression. Using an integrative approach between proteome and neurotransmitter profiles, we found that AD progression-dependent dopamine- and serotonin-related signaling modules are closely related to neurotransmitter changes, especially in the hippocampus and cerebellum. This integrative approach could provide new signaling modules to help understand AD progression and thereby enable improved treatment and clinical outcomes.},
}

@article {pmid42097395,
year = {2026},
author = {Shahsavari, F and Rajizadeh, MA and Pirmoradi, Z and Sabzalizadeh, M and Kohlmeier, KA and Soti, M and Shabani, M},
title = {Abscisic acid ameliorates cognitive deficits in an amyloid-β-induced mouse model of Alzheimer's disease associated with alterations in markers of neuroplasticity and neuroinflammation.},
journal = {Neuroscience letters},
volume = {},
number = {},
pages = {138619},
doi = {10.1016/j.neulet.2026.138619},
pmid = {42097395},
issn = {1872-7972},
abstract = {Abscisic acid (ABA, C15H20O4), a mammalian hormone, exhibits neuroprotective and anti-inflammatory properties. This study aimed to investigate the effects of ABA on the hippocampal-dependent processes: anxiety-, depression-like behaviors and cognitive impairments as well as levels of factors involved in neuroplasticity and neuroinflammation in an amyloid-β (Aβ)-induced mouse model of Alzheimer's disease (AD). One week following intracerebroventricular (i.c.v.) injection of Aβ1-42 in male mice, ABA was administered i.c.v. at doses of 10 or 15 µg/µl for 7 consecutive days. Behavioral assessments were conducted using the novel object recognition, open field, elevated plus maze, tail suspension, Morris water maze, and passive avoidance tests. Hippocampal gene expression levels of brain-derived neurotrophic factor (BDNF), N-methyl-D-aspartate receptor (NMDAR), and nuclear factor-κB (NF-κB) were evaluated using real-time PCR. ABA treatment significantly attenuated anxiety-like behaviors and improved spatial, avoidance and recognition memory deficits induced by Aβ1-42 administration with more behavioral domains affected at the 15 µg/µl dose. ABA induced significant upregulation in the hippocampus of NMDAR and BDNF expression and marked suppression of NF-κB in the ABA (15 µg/µl)-treated Aβ group, which could have played a mechanistic role in improvements in behaviors controlled by this structure. Histological analysis demonstrated attenuation of neuronal degeneration and pyknosis in the hippocampal CA1 region following ABA intervention. Collectively, these findings suggest that ABA ameliorates anxiety-related behaviors and cognitive impairments in an experimental mouse model of AD, potentially through modulation of neuroinflammatory and neuroplasticity-related pathways.},
}

@article {pmid42083975,
year = {2026},
author = {Saffold, K and Tall, A and Lowery, AT and Pryor, T and Jones-Muhammad, M and Shao, Q and Warrington, JP},
title = {Mouse Offspring Exposed to Preeclampsia/Eclampsia-like Symptoms Exhibit Cerebral Hypoperfusion & Mild Cognitive Impairment at 2 months of age.},
journal = {American journal of physiology. Heart and circulatory physiology},
volume = {},
number = {},
pages = {},
doi = {10.1152/ajpheart.00711.2025},
pmid = {42083975},
issn = {1522-1539},
support = {5R25HL145817//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; 1 R56 HL159447//HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI)/ ; P30GM103328//HHS | NIH | National Institute of General Medical Sciences (NIGMS)/ ; Startup/Bridge Funds from the Department of Neurology//University of Mississippi (UM)/ ; },
abstract = {Preeclampsia is a pregnancy complication characterized by high blood pressure and signs of organ damage, after the 20[th] week of pregnancy. Children born to mothers with preeclampsia or eclampsia (new-onset seizures during pregnancy) are more likely to develop learning and memory deficits and are more susceptible to neurovascular diseases compared to those born from normal pregnancies. The contributing mechanisms are unknown. In this study, we assessed whether exposure to reduced uteroplacental perfusion (RUPP), modeling placental hypoperfusion and preeclampsia, with or without pentylenetetrazol (PTZ) injection (to induce seizures and model eclampsia), results in cognitive impairment, Alzheimer's disease markers, and regional cerebral perfusion changes in adult offspring. On gestational day (GD)13.5, pregnant C57BL/6 mice (n=22) underwent Sham or RUPP surgery followed by injection or no treatment with PTZ (40 mg/kg) on GD18.5. At 2 months of age, spatial learning and cerebral perfusion were measured in randomly selected offspring or averaged to obtain mean data per sex, per litter (n=4-6 data points per group/treatment). RUPP-exposed offspring took a longer distance and made more errors navigating the Barnes maze. Cerebral perfusion was reduced in offspring exposed to RUPP, specifically in the prefrontal cortex, superior sagittal sinus, and whole brain. There was a significant reduction in perfusion in seizure-exposed offspring in the superior sagittal and transverse sinuses, whole brain, and cerebellum. Our results support the hypothesis that exposure to preeclampsia/eclampsia-like symptoms leads to mild learning impairment through reduced cerebral perfusion to cortical regions and decreased drainage of waste from the brain via the cerebral sinuses.},
}

@article {pmid42083983,
year = {2026},
author = {Au, R and Gifford, KA and Paschalidis, IC and Wighton, P and Levin, M and Imam, F and Bose, N and Pratap, A},
title = {The myth of digital biomarkers in Alzheimer's disease: how to make them a reality.},
journal = {Current opinion in psychiatry},
volume = {},
number = {},
pages = {},
pmid = {42083983},
issn = {1473-6578},
abstract = {PURPOSE OF REVIEW: With an estimated 41.1B digital devices, the term "digital biomarkers" has been increasingly bandied about in the research literature. There is, however, a significant disconnect between the presumption of digital biomarkers and the reality of digital biomarkers.

RECENT FINDINGS: The research literature embraces the concept of digital biomarkers without concomitant evidence for validation of digital measures as biomarkers. Unlike imaging or blood-based biomarkers, there is a woeful lack of research dedicated to validating digital measures as biomarkers. This gap also presents an opportunity. Regulatory agencies worldwide have long-standing protocols used by pharmaceutical and biotech companies to stand up quality management systems (QMS) that track research from inception to regulatory approved submissions. The recent United States (US) Food and Drug Administration (FDA) approval of Alzheimer's disease (AD) plasma biomarkers is another example where successful QMS implementation provided the processes and transparency necessary to obtain approval. Regulatory guidelines for digital technology validation are more circumspect on validation pathways of AD digital biomarkers, but FDA provides a framework for building a QMS that could potentially do so.

SUMMARY: Building an open source QMS for AD digital biomarker validation will be a critical breakthrough for harnessing the potential of digital technologies for detection, monitoring and treatment of AD and related disorders.},
}

@article {pmid42084750,
year = {2026},
author = {Hafez, MM and Abbas, HA and Shoman, NA and Soubh, AA and Aly, O and Sallam, MF and Seliem, M and Malaak, FA},
title = {A new era in neuropharmacology: assessing the efficacy and safety of novel anti-amyloid and non-amyloid drug targets for Alzheimer's disease.},
journal = {Journal of neurology},
volume = {273},
number = {5},
pages = {},
pmid = {42084750},
issn = {1432-1459},
mesh = {Humans ; *Alzheimer Disease/drug therapy/metabolism ; *Neuropharmacology/trends/methods ; *Amyloid beta-Peptides/metabolism/antagonists & inhibitors ; *Antibodies, Monoclonal/therapeutic use/pharmacology ; Animals ; },
abstract = {BACKGROUND: Alzheimer disease (AD) is the most common cause of dementia in the world with the prevalence expected to increase threefold to 152.8 million people by 2050. The current medications provide a short-term ameliorative effect, and this requires development of disease-modifying treatments, which address the biological pathogenesis.

METHODS: This review assesses the changing neuropharmacological environment offering a critical analysis of anti-amyloid monoclonal antibodies and investigates the so-called expanding frontier of non-amyloid targets. It also examines the approaches of clinical trials and the trend of biomarker-based patient selection and precision medicine.

RESULTS: Although β-site APP-cleaving enzyme 1 (BACE1) and secretase inhibitors did not achieve success in clinical trials because of mechanism-based toxicity and cognitive impairment, new monoclonal antibodies such as lecanemab and donanemab have shown high amyloid plaque clearance and reduced cognitive deterioration. Nevertheless, the treatments are associated with amyloid-related imaging abnormalities (ARIA). In addition to amyloid, studies are focusing on tau hyperphosphorylation, neuroinflammation through triggering receptor on myeloid cells 2 (TREM2) and NLR family pyrin domain containing 3 (NLRP3) and growth factor-mediated synaptic plasticity through brain-derived neurotrophic factor (BDNF).

CONCLUSIONS: AD treatment has entered the new era that demands a paradigm shift from monotherapies to multi-target cocktails. The future lies in precision neuropharmacology, where genetic stratification and individual biomarker analysis are used to provide the correct treatment at the most appropriate biological stage.},
}

Humans
*Alzheimer Disease/drug therapy/metabolism
*Neuropharmacology/trends/methods
*Amyloid beta-Peptides/metabolism/antagonists & inhibitors
*Antibodies, Monoclonal/therapeutic use/pharmacology
Animals

@article {pmid42084972,
year = {2026},
author = {Kumar, D and Singh, SB and Sagar, V and Prasad, MK and Kapoor, N and Mukul, A and Nishant, A},
title = {Breakthrough Vaccines and Transformative Therapies on the Horizon of Progress toward Diabetes Management.},
journal = {Indian journal of public health},
volume = {},
number = {},
pages = {},
doi = {10.4103/ijph.ijph_102_25},
pmid = {42084972},
issn = {0019-557X},
abstract = {Diabetes mellitus (DM) affects millions of people globally. Over the years, diabetes has emerged as a significant global health concern, with steadily increasing prevalence. This review explores the various aspects of DM and delves into the evolving field of new emerging treatments and diabetes vaccines, highlighting the potential they hold in revolutionizing diabetes management in the future. Therefore, it is imperative to know about the potential vaccines and novel emerging treatment options for DM and to understand the challenges faced in making novel therapies. It is also needed to recognise the intricate relationship between diabetes and Alzheimer's disease, an emerging entity known as type 3 diabetes. Literature search was done in PubMed database, and relevant articles were selected for the narrative review. The review reveals that currently, most vaccines that have been developed are in animal studies and early phases of trials. Only few human trials have been conducted, but, with positive outcome. There are also some novel therapeutics emerging as potential management options for diabetes. There are evidences to support that Alzheimer's disease can rightly be called type 3 diabetes. In conclusion, there is a growing interest in the development of vaccines as a revolutionary approach to diabetes management. As our understanding of diabetes deepens and vaccine technology advances, the prospect of a diabetes vaccine becoming a reality offers hope for millions living with this condition and in reducing the burden of diabetes-related complications.},
}

@article {pmid42086977,
year = {2026},
author = {Khan, TTS and Wong, CYJ and Sheikh, Z and Fathi, A and Maleknia, S and Oveissi, F and Abrams, T and Knox, W and van der Hoven, J and Antonito, A and Murray, M and Svolos, M and Suman, J and Tietz, O and Ong, HX and Traini, D},
title = {Repurposing insulin for Alzheimer's disease treatment: intranasal delivery of a thermoresponsive nanocarrier-based insulin formulation to the brain.},
journal = {Drug delivery and translational research},
volume = {},
number = {},
pages = {},
pmid = {42086977},
issn = {2190-3948},
abstract = {The Intranasal route provides an effective pathway for insulin delivery to the brain compared to oral/subcutaneous routes as it provides direct access to the brain, bypassing the restrictive blood-brain barrier (BBB), while minimizing systemic exposure. The present study investigated the potential of a thermoresponsive polymer, PNPHO, as a nanocarrier for brain-targeted insulin delivery through the intranasal route, with the aim of repurposing insulin for Alzheimer's disease treatment. Insulin-loaded nanoparticles (NP) were formulated using an advanced crossflow mixing technology with lower (F1) and higher (F2) PNPHO concentrations and characterised in vitro for size, zeta potential, encapsulation efficiencies, stability, drug deposition, and transport and in vivo for biodistribution. Both F1 and F2 NP demonstrated particle sizes ranging from 35.9 to 49.8 nm with low polydispersity index (< 0.3), negative surface charges, high encapsulation efficiencies (> 99%), and conserved structural integrity post 4 weeks of stability study. NP demonstrated significantly greater in vitro nasal deposition compared to insulin alone. Notably, the PNPHO nanocarrier protected insulin from enzymatic degradation, overcoming a key barrier associated with protein/peptide delivery. In vitro drug transport studies showed an initial delay in NP transport across nasal cells due to PNPHO-mucoadhesive properties, followed by increased transport. Significantly enhanced time-dependent NP transport across the BBB cells compared to insulin alone (p < 0.0001) confirmed NP's ability to cross the BBB. In vivo, NP demonstrated prolonged nasal retention and higher brain: serum ratio in mice, suggesting sustained drug release and improved brain delivery compared to insulin alone. Collectively, the study highlight the potential of PNPHO as a promising nanocarrier for achieving targeted and efficient intranasal delivery of insulin to the brain.},
}

@article {pmid42087592,
year = {2026},
author = {Liu, X and Xu, H and Zhao, Y and Yang, J and Zhang, L and Wang, Z and Lim, K and Zhang, C and Lu, L},
title = {Roles of POU3F2 in Brain Development and Neuropsychiatric Disorders.},
journal = {Developmental neurobiology},
volume = {86},
number = {3},
pages = {e70034},
doi = {10.1002/dneu.70034},
pmid = {42087592},
issn = {1932-846X},
support = {202200331//Cooperative Research Project/ ; //Shanxi Province Higher Education/ ; 82571379//National Natural Science Foundation of China/ ; },
mesh = {Animals ; Humans ; *Brain/growth & development/metabolism ; *Mental Disorders/metabolism/genetics ; *POU Domain Factors/metabolism/genetics ; *Homeodomain Proteins/metabolism ; *Nerve Tissue Proteins/metabolism ; },
abstract = {POU3F2, a member of the Pit-Oct-Unc (POU) domain transcription factor family, is widely expressed in the central nervous system and essential for the development and maturation of brain. POU3F2 deletion results in impaired hypothalamus and neocortex development, and most mice die between postnatal days 0 and 10. Recently, emerging evidences have demonstrated that POU3F2 is involved in neuropsychiatric disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, bipolar disorder, schizophrenia, and autism spectrum disorder, albeit still with some limitations in current studies. Besides, POU3F2 also plays a vital role in the reprogramming of somatic cells into neuronal lineages, which provides new ideas and directions for the treatment of neuropsychiatric disorders. This review aims to systematically summarize and analyze the diverse roles of POU3F2 in brain development, neuropsychiatric disorders, and neuronal reprogramming. Furthermore, the potential of POU3F2-targeted therapies for neuropsychiatric disorders and proposed key questions for future research are also emphasized. POU3F2 plays a pivotal role in brain development, the pathogenesis of neurological and psychiatric disorders, and the reprogramming of neural cells. A more comprehensive and systematic understanding of its molecular mechanism might provide novel therapeutic approaches for neuropsychiatric disorders.},
}

Animals
Humans
*Brain/growth & development/metabolism
*Mental Disorders/metabolism/genetics
*POU Domain Factors/metabolism/genetics
*Homeodomain Proteins/metabolism
*Nerve Tissue Proteins/metabolism